Melanocortin receptor agonists

ABSTRACT

The present invention relates a compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof effective as agonist of melanocortin receptor, and an agonistic composition of melanocortin receptor comprising the same as active ingredient.

TECHNICAL FIELD

The present invention relates to a compound of the following formula 1, pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof effective as an agonist for melanocortin receptor.

in which

R¹, R², R³, R⁴, R⁵, n and m are defined as described below.

BACKGROUND ART

Five subtypes of receptors have been cloned and characterized in the melanocortin family. These G-protein coupled receptors (GPCR) stimulate the cAMP signal transduction pathway in many different tissues, mediating a wide range of physiological functions. Melanocortin 1 receptor (MC1R) is mainly expressed in melanocytes, monocytes, and mast cells, to mediate pigmentation of the hair and skin and to block inflammation. MC2R is expressed in adipocytes and adrenal cells, to mediate steroidogenesis in the adrenal gland. MC3R is present in the brain, hyphothalamus, heart, gut, and placenta, and has been associated with energy homeostasis and inflammation. MC4R is uniquely expressed in the brain, and controls feeding behavior, energy homeostasis, and erectile function. MC4R knock-out mice revealed the phenotype of hyperphasia and obesity. MC5R is found in a wide range of tissues and is considered to play a role for the exocrine gland system.

With a plethora of physiological functions of melanocortin receptors, a large number of compounds have been designed and synthesized in search for potent agonists and antagonists.

Early examples are synthetic peptides and peptide analogues that have been identified on the basis of endogenous agonist such as αMSH. These peptide agonists have been used to characterize the function of these receptors. NDP-αMSH is a highly potent and nonselective agonist of MC1R, 3R, 4R and 5R, and has been reported to attenuate food intake and body weight gain in rat models. A cyclic heptapeptide MT-II is an agonist with a similar non-selective profile, and its therapeutic use has been proven in clinical trials for the treatment of erectile dysfunction. HP-228, a peptide analogue with similar affinity for all four receptors, was in clinical trials for the treatment of pain and inflammation associated with surgery.

Several small molecule agonists for the melanocortin receptors have been discovered to have significant activity in drug trials to search MC4R agonists for the treatment of obesity, sexual dysfunction or inflamation. For example, the Merck research group has discovered a series of potent and selective MC4R agonists, one of which demonstrated significant effect for augmenting erectile response in mice (J. Med. Chem. 2002, 45, 4849). The Chiron research group has discovered a series of guanidine compounds as agonists that have hyphophasic activity and thus anti-obesity effect in the ob/ob mouse model (WO 02/18327). On the other hand, the Bristol-Myers Squibb group has discovered a highly potent selective MC 1R agonist, which showed efficacy in an acute mouse model of inflammation (J. Med. Chem. 2003, 46, 1123).

In view of the unresolved deficiencies of the various pharmaceutical compounds as discussed above, there is continuing need in the art for small molecule MCR agonists and pharmacological compositions that have improved pharmacological profiles. It is, therefore, an object of the present invention to provide novel compounds that are useful for the treatment of obesity, diabetes, sexual dysfunction, and inflammation.

Specifically, the present invention provides a compound of formula 1 having agonistic effect against MCRs, in particular selective agonistic effect against MCR4, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof.

Another object of the present invention is to provide a melanocortin receptor agonistic composition comprising the compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof, as active ingredients, together with pharmaceutically acceptable carrier.

In particular, the composition according to the present invention has potent effect for the prevention and treatment of diabetes, erectile dysfunction, obesity, and inflammation.

DISCLOSURE OF THE INVENTION

The present invention relates to a compound of the following formula 1, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof.

in which m and n each independently represents 1 or 2, R¹ reperesents

hydrogen,

—(CH₂)_(p)—R⁶,

—(CH₂)_(p)—CO—(CH₂)_(p)—R⁶,

—(CH₂)_(p)—CO—(CH₂)_(p)—CH(R⁶)(R¹⁰), or

—(CH₂)_(p)—SO₂—(CH₂)_(p)—R⁶,

wherein

p independently represent 0, 1, 2, or 3,

R⁶ represents C₁-C₁₀-alkyl, C₁-C₈-alkoxy, C₃-C₈-cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by one or more substituents selected from the group consisting of C₁-C₁₀-alkyl, C₁-C₁₀-dialkyl, C₃-C₁₃-cycloalkyl, C₃-C₁₃-dicycloalkyl, C₃-C₁₃-tricycloalkyl, perhalo-C₁-C₈-alkyl, aryl, heteroaryl, heterocycle, hydroxy, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkoxy, trifluoromethoxy, aryl-C₁-C₈-alkyloxy, aryloxy, oxo, mercapto, C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, C₁-C₈-alkylsulfonyl, arylsulfonyl, C₁-C₈-alkylthio, arylthio, cyano, formyl, halogen, carbonyl, thiocarbonyl, C₃-C₈-cycloalkylcarbonyl, arylcarbonyl, ar-C₁-C₈-alkyl, ar-C₁-C₈-alkylcarbonyl, ar-C₁-C₈-alkylsulfonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, carbamoyl, C₁-C₈-alkylcarbamoyl, di(C₁-C₈-alkyl)carbamoyl, O-sulfoneamido, N-sulfonamido, carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, trihalomethanesulfonyl, amino, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, and protective derivatives thereof,

R¹⁰ represents heterocycle, or represents amino or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷,

wherein,

R⁷ represents halogen, amino, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, hydroxy, C₁-C₈-alkoxy, trifluoromethoxy, C₁-C₆-alkylcarbonyl, carboxy, C₁-C₈-alkyl, mercapto, C₁-C₁₀-alkylthio, phenoxy, C₁-C₈-alkoxycarbonyl, arylcarbonyl, carbamoyl, C₁-C₆-alkylsulfonyl, arylsulfonyl, cyano or oxo,

R⁶ and R¹⁰ may form 5- or 6-membered single ring together with the atoms to which they attached,

hydrogen atom in —(CH₂)_(p)— group can be replaced by R⁶,

R¹ represents

hydrogen,

C₁-C₈-alkyl which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷,

C₃-C₇-cycloalkyl, or

—CO—(CH₂)_(p)—R⁶,

R¹ and R² together with the atoms to which they attached, may form 4- or 8-membered single ring or two ring which can contain heteroatom selected from the group consisting of O, S and N—(C₁-C₄-alkyl),

R³ and R⁴ each independently represents

hydrogen,

C₁-C₈-alkyl,

—(CH₂)_(p)—C₃-C₈-cycloalkyl,

—(CH₂)_(p)—C₆-C₁₀-aryl,

—(CH₂)_(p)-heteroaryl, or

—(CH₂)_(p)-heterocycle,

wherein, alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷,

R⁵ represents

hydrogen,

C₁-C₆-alkyl,

—(CH₂)_(p)—CO—R⁸,

—(CH₂)_(p)—C(O)N(R⁸)(R⁹),

—(CH₂)_(p)—C(S)N(R⁸)(R⁹),

—(CH₂)_(p)—SO₂—N(R⁸)(R⁹), or

—(CH₂)_(p)—SO₂—R⁸,

wherein,

R⁸ and R⁹ each independently represents

hydrogen,

C₁-C₈-alkyl,

C₁-C₆-alkoxy,

C₁-C₆-alkylthio,

C₃-C₇-cycloalkyl,

C₃-C₇-cycloalkenyl,

heterocycle,

aryl, or

heteroaryl,

wherein

alkyl, cycloalkyl, or aryl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷, C₃-C₈-cycloalkyl, heterocycle, hydroxy-C₁-C₈-alkyl, halogen-C₁-C₈-alkyl, C₁-C₈-alkoxy-C₁-C₈-alkyl, amino-C₁-C₈-alkyl, C₃-C₈-cycloalkyloxy, ar-C₁-C₈-alkyloxy, aryloxy, arylthio, formyl, C₁-C₈-alkylcarbamoyl, di(C₁-C₈-alkyl)carbamoyl, C₁-C₈-alkylcarbonyloxy, C₁-C₈-alkoxy-C₁-C₈-alkoxy, C₃-C₈-cycloalkylcarbonyl, ar-C₁-C₈-alkylcarbonyl, C₂-C₈-alkanoyloxy, C₃-C₈-cycloalkylcarbonyloxy, arylcarbonyloxy which is unsubstituted or substituted by halogen, ar-C₁-C₈-alkylcarbonyloxy, C₁-C₈-alkoxyimino, ar-C₁-C₈-alkylsulfonyl, and C₁-C₈-alkylsulfonyloxy,

heterocycle, cycloalkenyl, or heteroaryl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷, and hydroxy-C₁-C₈-alkyl,

R⁴ and R⁵ together with the atoms to which they attached, may form 4- or 8-membered single ring or two ring which can contain heteroatom selected from the group consisting of O, S and N—(C₁-C₄-alkyl).

In the radical definitions of the compound of formula (1) according to the present invention, the term “alkyl” means straight-chain or branched hydrocarbon radical when used alone or in combination with hetroatoms such “alkyloxy.”

The term “cycloalkyl” represents unsaturated aliphatic ring including cyclohexyl.

The term “aryl” represents 6- to 10-membered aromatic group including phenyl, naphthyl, etc.

The term “heteroaryl” includes 1 to 2 heteroatom(s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents aromatic 3- to 6-membered ring which can be fused with benzo or C₃-C₈-cycloalkyl. Examples of monocyclic heteroaryl are, but are not limited to, thiazole, oxazole, thiophene, furane, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimnidine, pyrazine, and similar group to them. Examples of acyclic heteroaryl are, but are not limited to, indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine, and similar group to them.

The term “heterocycle” includes 1 to 2 heteroatom(s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents 4- to 8-membered ring which can be fused with benzo or C₃-C₈-cycloalkyl, and which is saturated or has 1 or 2 of double bond. Its examples are, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and similar group to them.

Preferred compounds among the compounds of formula 1 above are those

wherein

i) R¹ represents hydrogen, —(CH₂)^(p)—R⁶, —(CH₂)_(p)—CO—R⁶, —CO—(CH₂)_(p)—R⁶, —(CH₂)_(p)—CO—(CH₂)_(p)—CH(R⁶)(R¹⁰), or —SO₂—(CH₂)_(p)—R⁶,

R⁶ represents C₁-C₁₀-alkyl, C₁-C₈-cycloalkyl, heterocycle, aryl, or heteroaryl, or represent amino or hydroxy,

hydrogen atom in —(CH₂)_(p)— group can be replaced by R⁶,

wherein

C₁-C₁₀-alkyl, C₁-C₈-cycloalkyl, heterocycle, aryl, or heteroaryl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷,

amino or hydroxy is unsubstituted or mono- or di-substituted by the substituents selected from the group consisting of C₁-C₁₀-alkyl, ar-C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₂-C₈-alkylcarbonyl, C₃-C₈-cycloalkylcarbonyl, arylcarbonyl, ar-C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, carbamoyl, di(C₁-C₈-alkylcarbamoyl, C₁-C₈-alkylsulfonyl, arylsulfonyl, and ar-C₁-C₈-alkylsulfonyl,

R¹⁰ is defined as the above description,

R⁶ and R¹⁰ may form 5- or 6-membered single ring together with the atoms to which they attached,

preferably, R¹ represents hydrogen, —(CH₂)_(p)—R⁶, —(CH₂)_(p)—CO—R⁶, —CO—(CH₂)_(p)—R⁶ or —(CH₂)_(p)—CO—(CH₂)_(p)—CH(R⁶)(R¹⁰),

more preferably, R¹ represents hydrogen, —R⁶ or —CO—CH(R⁶)(R¹⁰),

R¹⁰ represents heterocycle, or represents amino or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷,

R⁶ and R¹⁰ may form 5- or 6-membered single ring together with the atoms to which they attached,

ii) R² represents hydrogen or C₁-C₆-alkyl,

iii) R³ represents C₁-C₈-alkyl, —(CH₂)_(p)—C₃-C₇-cycloalkyl, —(CH₂)_(p)-phenyl, or —(CH₂)_(p)-heteroaryl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of R⁷,

preferably, R³ represents —CH₂-cyclohexyl or —CH₂-phenyl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of halogen, cyano, hydroxy, C₁-C₈-alkoxy, trifluoromethoxy and C₁-C₄-alkyl,

more preferably, R³ represents —CH₂-phenyl, in which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of chloro, bromo, cyano, hydroxy, methoxy and metyhl,

iv) R⁴ represents C₁-C₈-alkyl, or represent C₃-C₈-cycloalkyl, phenyl, heteroaryl, or heterocycle, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of R⁷,

preferably, R⁴ represents C₃-C₈-cycloalkyl or phenyl,

more preferably, R⁴ represents cyclohexyl, cylcoheptyl or cylcopentyl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of methyl, ethyl, t-butyl, hydroxy and oxo, or represent phenyl unsubstituted or mono- to tri-substituted by substituents from the group consisting of fluoro, chloro, methoxy and methyl,

v) R⁵ represents hydrogen, C₁-C₆-alkyl, —(CH₂)_(p)—CO—R⁸, —(CH₂)_(p)—C(O)N(R⁵)⁹), or —(CH₂)_(p)—SO₂—R⁸,

preferably, R⁵ represents —CO—R⁸ or —C(O)N(R⁸)(R⁹),

more preferably, R⁸ and R⁹ each independently represents hydrogen, methoxy, amino, C₁-C₈-alkyl, C₃-C₆-cycloalkyl, C₅-C₆-cycloalkenyl, heterocycle, or phenyl,

wherein, C₁-C₈-alkyl or C₃-C₆-cycloalkyl is unsubstituted or mono-substituted by the substituents selected from the group consisting of methyl, hydroxy, amino, C₁-C₄-alkoxy, phenoxy, benzyloxy, fluoro, phenylsulfoxy, acetyl, methoxymethylalkoxy, carboxy, formyl, methoxycarbonyl, dimethylcarbamoyl, carboxy, phenylcarbonyloxy, methoxycarbonyl, difluorophenylcarbonyloxy, dimethylphenylcarbonyloxy, cyclohexylcarbonyloxy, arylcarbonyloxy, and oxo,

C₅-C₆-cycloalkenyl represents cyclopentyl or cyclohexyl substituted by hydroxy or amino,

heterocycle or phenyl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of hydroxy, methyl, amino, nitrobenzenesulfonyl, and oxo.

vi) R¹ represents hydrogen, —R⁶ or —CO—CH(R⁶)(R¹⁰),

R¹⁰ represents heterocycle, or represents-amino or hydroxy, in each of which is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of R⁷,

R⁶ and R¹⁰ may form 5- or 6-membered single ring together with the atoms to which they attached,

R³ represents —CH₂-phenyl, in which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of chloro, bromo, cyano, hydroxy, methoxy and metyhl,

R⁴ represents cyclohexyl, cylcoheptyl or cylcopentyl, in each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of methyl, ethyl, t-butyl, hydroxy and oxo, or represent phenyl unsubstituted or mono- to tri-substituted by substituents from the group consisting of fluoro, chloro, methoxy and methyl,

R⁵ represents —CO—R⁸ or —C(O)N(R⁶)(R⁹),

R⁸ and R⁹ each independently represents hydrogen, methoxy, amino, C₁-C₈-alkyl, C₃-C₆-cycloalkyl, C₅-C₆-cycloalkenyl, heterocycle, or phenyl,

wherein, C₁-C₈-alkyl or C₃-C₆-cycloalkyl is unsubstituted or mono-substituted by the substituents selected from the group consisting of methyl, hydroxy, amino, C₁-C₄-alkoxy, phenoxy, benzyloxy, fluoro, phenylsulfoxy, acetyl, methoxymethylalkoxy, carboxy, formyl, methoxycarbonyl, dimethylcarbamoyl, carboxy, phenylcarbonyloxy, methoxycarbonyl, difluorophenylcarbonyloxy, dimethylphenylcarbonyloxy, cyclohexylcarbonyloxy, arylcarbonyloxy, and oxo,

C₅-C₆-cycloalkenyl represents cyclopentyl or cyclohexyl substituted by hydroxy or amino,

heterocycle or phenyl is unsubstituted or mono- or poly-substituted by the substituents selected from the group consisting of hydroxy, methyl, amino, nitrobenzenesulfonyl, and oxo.

Representative compounds of formula 1 according to the present invention include the compounds listed in the following Table 1.

TABLE 1 R¹ R² R³ *1 n m R⁴ *2 R⁵ H H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ H H 4-Cl-Bn R 2 1 c-Hex S C(O)OMe H H 4-Cl-Bn R 2 1 c-Hex S C(O)N(Me)₂ H H 4-Cl-Bn R 2 1 c-Hex S SO₂Me H H 4-Cl-Bn R 2 1 c-Hex S CH₂C(O)OMe H H 4-CI-Bn R 2 1 c-Hex S SO₂NH₂ H H 4-Cl-Bn R 2 1 c-Hex S Gly H H 4-Cl-Bn R 2 1 c-Hex S CH₂C(O)N(Me)₂ H H 4-Cl-Bn R 2 1 c-Hex S CH₂SO₂Me H H 4-Cl-Bn R 2 1 c-Hex R C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 c-Hex R C(O)C(Me)₃ H H 4-Cl-Bn R 2 1 c-Hex S C(O)[(R)—CH(Me)CH₂OH] H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂)₂—OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)—(CH₂OH)₂ H H 4-Cl-Bn R 2 1 c-Hex R C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OMe H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OBn H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(—(CH₂)₄—)CH₂OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂)₃O-(2,4-diMe—Ph) H H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)CH₂OAc H H 4-Cl-Bn R 2 1 c-Hex S C(O)C[—(CH₂)₂—]CH₂OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(Pr) H H 4-Cl-Bn R 2 1 c-Hex S C(O)NHEt H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(Bu) H H 4-Cl-Bn R 2 1 c-Hex S C(O)(3-HO—Ph) H H 4-Cl-Bn R 2 1 c-Hex S C(O)(4-HO—Ph) H H 4-Cl-Bn R 2 1 c-Hex S C(O)[2-(CH₂OH)-1-(c-penten)-1-yl] H H 4-Cl-Bn R 2 1 c-Hex S C(O)[2-(CH₂OH)-1-(c-hexen)-1-yl] H H 4-Cl-Bn R 2 1 c-Hex S C(O)[1-Nos-Pid-4-yl] H H 4-Cl-Bn R 2 1 c-Hex S C(O)[Pid-4-yl] H H 4-Cl-Bn R 2 1 c-Pen S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 c-Hep S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 i-Pr S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 c-Hex-CH₂ S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 c-Pen R C(O)CH(Me)₂ H H 4-Cl-Bn S 2 1 c-Hex S C(O)CH(Me)₂ H H Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH H H 4-Br-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-Br-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH H H 4-MeO-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-MeO-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH H H 3,4-diCl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-F-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-F-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH H H 4-Me-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH H H 4-HO-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H (c-Hex)-CH₂ R 2 1 c-Hex S C(O)CH(Me)₂ H H (indol-2-yl)-CH₂ R 2 1 c-Hex S C(O)CH(Me)₂ H H i-Bu R 2 1 c-Hex S C(O)CH(Me)₂ H H NH₂C(O)CH₂— R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 2,3-diF—Ph S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 2,4-diF—Ph S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 2,3-diF—Ph R C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 2,4-diF—Ph R C(O)CH(Me)₂ H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(CH₂)₄NH₂ H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(CH₂)₃NH₂ H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(CH₂)₂NH₂ H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(CH₂)₂OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)NH(CH₂)₂OMe H H 4-Cl-Bn R 2 1 c-Hex S C(O)[(3S)-3-(OH)-Pyd-1-yl] H H 4-Cl-Bn R 2 1 c-Hex S C(O)[(2S)-2-(HOCH₂)-Pyd-1-yl] H H 4-Cl-Bn R 2 1 c-Hex R C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 c-Hex R C(O)C(Me)CH₂OH H H 4-Cl-Bn R 2 1 2,3-diF—Ph S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 3,5-diMe—Ph R,S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 2,3-diF-ph R,S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-Me—Ph R,S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(Q)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-t-Bu-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4,4-diF-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-F-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-trans-Et-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-cis-Et-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-oxo-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-OH-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 Spiro[2.5]octane S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-Pid-1-yl S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 4-Ph-c-Hex S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 Ph R,S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 2-adamantyl S C(O)C(Me)₂CH₂OH H H 4-F-Bn R 2 1 c-Hex S C(O)[(R)—CH(Me)CH₂OH] H H 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] H H 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] H H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)[C(Me)(CH₂—OH)₂] H H 4-Cl-Bn R 2 1 c-Hex S C(O)[C(OH)(i-Pr)] H H 4-Cl-Bn R 2 1 c-Hex S C(O)[CH₂C(Me)₂—OH] H H 4-Cl-Bn R 2 1 c-Hex S C(O)(—(CH₂)₂—)C(O)OH H H 4-Cl-Bn R 2 1 c-Hex S C(O)(—(CH₂)₂—)C(O)OMe H H 4-Cl-Bn R 2 1 Pid-4-yl S C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 1 c-Hex S 2-(CH₂OH)-1-(c-peten)1-yl H H 4-Cl-Bn R 2 1 c-Hex S 2-(CH₂OH)-1-(c-hexen)1-yl H H 4-Cl-Bn R 2 1 c-Hex S C(O)N[(CH)₂OH]₂ H H 4-Cl-Bn R 2 1 c-Hex S C(O)N[(CH)₃OH]₂ Me H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ Me H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 c-Hex R C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-t-Bu-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4,4-diF-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 Spiro[2.5]octane S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-F-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-trans-Et-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-cis-Et-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me H 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(—CH₂CH₂)CH₂OH Me H Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Me H 4-F-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Me-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Me H 4-MeO-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH i-Pr H 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] i-Pr H 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] i-Pr H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)[C(Me)(CH₂—OH)₂] i-Pen H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Me Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ Me Me 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ Me Me 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Me Me 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(O)C(Me)₂CH₂OH Me Me 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)C(Me)₂CH₂OH Me Me 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)C(Me)₂CH₂OH Me Me 4-Cl-Bn R 2 1 4-trans-Et-c-Hex S C(O)C(Me)₂CH₂OH Me Me 4-Cl-Bn R 2 1 4-cis-Et-c-Hex S C(O)C(Me)₂CH₂OH Me H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)(CH₂—OH)₂ Me H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OMe) Me H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OMOM) i-Pr Me 4-Cl-Bn R 2 1 c-Hex S C(O)[(R)—CH(Me)CH₂OH] Me Me 4-Cl-Bn R 2 1 c-Hex S C(O)[(R)—CH(Me)CH₂OH] Me Me 4-Cl-Bn R 2 1 c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me Me 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)(—CH₂OC(O)OCH₂—) Me Me 4-Cl-Bn R 2 1 4-trans-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me Me 4-Cl-Bn R 2 1 4-cis-Me-c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me Me 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)[C(Me)(CH₂—OH)₂] Me Me Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OH) Me Me 4-F-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OH) Me Me 4-Me-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OH) Me Me 4-MeO-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OH) Me Me 4-MeO-Bn R 2 1 4-t-Bu-c-Hex S C(O)C(Me)₂(CH₂—OH) Et Et 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH i-Pr H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH —(CH₂)₅— 4-MeO-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH MeO—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH HO(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Ac H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ MeSO₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (iPr)C(O) H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH EtC(O) H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)[(R)—CH(Me)CH₂OH] Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH HO(CH₂)₃C(O) H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH (Me)₂N-Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH i-Bu H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH —(CH₂)₄— 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH —(CH₂)₅— 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH NH₂—(CH₂)₄ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH HOCH₂C(Me)₂C(O) H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH imidazol-2-yl H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH imidazol-4-yl H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH HO(CH₂)₄ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH PrC(O) H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH Pyd-3-yl H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH (S)Pyd-2-CH₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH MeOC(O)CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH DTic H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH NH₂—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH (Me)HN—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH (S)Pyd-2-CH₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)[2-(CH₂OH)-1-(c-penten)-1-yl] (Me)₂NC(O)—CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ NH₂C(O)—CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ MeO₂C—CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ HO₂C—CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N—Me-Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N-diMe-Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N—Ac-Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N-Ms-Gly H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Ala H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ β-Ala H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ β-Ala H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ N—Me-β-Ala H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N-diMe-β-Ala H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ NH₂(CH₂)₄ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)Ala H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)His H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)His H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ N-Me-(S)His H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N-Ac-(S)His H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N-Ac-(S)His H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ N-Ms-(S)His H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)His H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)Phe H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Phe H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pro H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pro H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ N—Me-(R)Pro H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ (S)Pro H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pid-2-CO H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pid-2-CO H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ N—Me-(R)Pid-2-CO H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ N—Ac-(R)Pid-2-CO H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)Pid-2-CO H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Tic H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Tic H Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)Tic H 4-Cl-Bn R 2 1 c-Hex R C(O)CH(Me)₂ cis-Dic H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ HO—CH₂—C(O) H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ HO—C(O)CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH HO—C(O)CH₂ HO—C(O)CH₂ 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH MeOC(O)CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex R C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 2,3-diF—Ph R C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 2,4-diF—Ph R C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Pen S C(O)CH(Me)₂ (R)Pyd-2-CH₂ H Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pyd-2-CH₂ H (c-Hex)-CH₂— R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pyd-2-CH₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)-1-Me-Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)-1-Me-Pyd-2-CH₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)-1-Ac-Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)-1-Me-Pyd-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pid-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)-1-Me-Pid-2-CH₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)Pid-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (S)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ NH₂—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ NH₂—(CH₂)₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Me)N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Me)N—(CH₂)₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Me)N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex R C(O)CH(Me)₂ (Me)N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex R C(O)C(Me)₃ (Me)₂N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Me)₂N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₃ (Me)₂N—(CH₂)₂ H Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Me)₂N—(CH₂)₂ H (c-Hex)-CH₂— R 2 1 c-Hex S C(O)CH(Me)₂ (Me)₂N—(CH₂)₂ Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)2 (Me)N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)CH₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)(CH₂—OH)₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂[CH₂—N(Me)₂] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—OMe (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH₂—OMOM) (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—OBn (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂[CH₂—O(i-Bu)] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—OPh (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—SPh (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—OCOPh (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂[CH₂—OCO(c-Hex)] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—OCOBn (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂CH₂—OCOBu (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂[CH₂—OCO(i-Pr)] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂[CH₂—OCO(2,5diF—Ph)] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂OAc (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)[2-(HOCH₂)-1-(c-penten)-1-yl] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)[(3S)-3-(OH)-Pyd-1-yl] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CHO) (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 c-Hex S C(O)C(Me)₂(CH═N—OMe) (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 2,3-diF—Ph S C(O)C(Me)₂(CH₂—OH) (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 2,3-diF—Ph S C(O)N(Me)₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 4-cis-Mec-Hex S C(O)C(Me)₂CH₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 1 4,4-diMe-c-Hex S C(O)C(Me)₂CH₂OH AcNH—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Et)₂N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ [Me(Et)]N—(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (R)Pyd-3-yl H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂

H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ Pid-4-yl H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ Pid-4-yl Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ 1-Me-Pid-4-yl Me 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ (Me)₂N—CH═ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 1 c-Hex S C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)C(Me)₃ H H 4-Cl-Bn R 2 2 c-Hex C(O)OMe H H 4-Cl-Bn R 2 2 c-Hex CH₂C(O)OMe H H 4-Cl-Bn R 2 2 c-Hex CH₂C(O)N(Me)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)₂ H H 4-Cl-Bn R 2 2 c-Hex Gly H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)NH(i-Pr) H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(i-Pr) H H 4-Cl-Bn R 2 2 c-Hex C(O)NH(Bu) H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(Bu) H H 4-Cl-Bn R 2 2 c-Hex C(O)NH(c-Hex) H H 4-Cl-Bn R 2 2 c-Hex C(O)NHPh H H 4-Cl-Bn R 2 2 c-Hex C(S)NH(Et) H H 4-Cl-Bn R 2 2 c-Hex C(S)N(Me)(Et) H H 4-Cl-Bn R 2 2 c-Hex SO₂Me H H 4-Cl-Bn R 2 2 c-Pen C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 c-Hep C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2-MeO-Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 3-MeO-Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2-Cl-Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2-F-Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 3-F-Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 4-F-Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2,4-diF—Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2,5-diF—Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2,6-diF—Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 3,4-diF—Ph C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2-F-4-MeO-Ph C(O)CH(Me)₂ H H 4-Cl-Bn S 2 2 c-Hex C(O)CH(Me)₂ H H 4-Br-Bn R 2 2 c-Hex C(O)CH(Me)₂ H H 3,4-diCl-Bn R 2 2 c-Hex C(O)CH(Me)₂ H H 4-F-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ H H 4-HO-Bn R 2 2 c-Hex C(O)CH(Me)₂ H H 4-MeO-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ H H (c-Hex)-CH₂ R 2 2 c-Hex C(O)CH(Me)₂ H H 3,4-diCl-Bn R 2 2 c-Hex C(O)CH(Me)₂ H H 4-F-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ H H 4-HO-Bn R 2 2 c-Hex C(O)CH(Me)₂ H H 4-MeO-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ H H (c-Hex)-CH₂ R 2 2 c-Hex C(O)CH(Me)₂ H H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)N(Me)(CH₂)₂OH H H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)N(Me)(CH₂)₂OMe H H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)CH₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)[2-(CH₂OH)-1-(c-penten)-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[2-(CH₂OH)-1-(c-hexen)-1-yl] H H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe H H 4-Cl-Bn R 2 2 c-Hex C(O)NH(CH₂)₂OMe H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OMe H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe]₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)OMe H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)[C(Me)₂CH₂NH₂] H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂F H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂F H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₃OH]₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₃OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₃OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F]₂ H H 4-F-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe H H 4-F-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OH H H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH H H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F H H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F H H 4-F-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂OH H H 4-F-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH H H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH H H 4-F-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe H H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂F H H 4-F-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂F H H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH H H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₃OH H H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F]₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)[(3S)-3-(OH)-Pyd-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(3R)-3-(OH)-Pyd-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(2R)-2-(HOCH₂)-Pyd-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(2S)-2-(HOCH₂)-Pyd-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(3R)-3-amino-Pyd-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(3S)-3-amino-Pyd-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(3R)-3-(OH)-Pid-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[(3S)-3-(OH)-Pid-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[4-(OH)-Pid-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)[4-amino-Pid-1-yl] H H 4-Cl-Bn R 2 2 c-Hex C(O)(—(CH₂)₂—)C(O)OH H H 4-Cl-Bn R 2 2 c-Hex C(O)(—(CH₂)₂—)C(O)OMe H H 4-Cl-Bn R 2 2 4-cis-Me-c-Hex C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 2 4-trans-Me-c-Hex C(O)C(Me)₂CH₂OH H H 4-Cl-Bn R 2 2 4-diMe-c-Hex C(O)(—(CH₂)₂—)C(O)OMe H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F H H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ H H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)[C(O)(Me)₂CH₂OH] Me H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ Me H 4-Cl-Bn R 2 2 c-Hex C(O)C(Me)₃ Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH Me Me 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₃OH Me Me 4-F-Bn R 2 2 c-Hex C(O)N(Et)₂ Me Me 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH Me Me 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH Me Me 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ Me Me 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe Me Me 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH MeO₂C—CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ HO₂C—CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ N-diMe-Gly H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Ala H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ β-Ala H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ N-diMe-β-Ala H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (S)His H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pro H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ N-Me-(R)Pro H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Tic H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ MeO₂C—CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ HO₂C—CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ N-diMe-Gly H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Ala H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ β-Ala H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ N-diMe-β-Ala H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (S)His H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pro H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ N-Me-(R)Pro H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Tic H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)C(Me)₃ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,4-diF—Ph C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-F-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (2R,4S)-4F-Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (R)Pyd-2-CH₂— H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)C(Me)₂CH₂OH (R)Pyd-2-CH₂— H 4-Cl-Bn R 2 2 c-Hex C(O)C(Me)₂CH₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)OMe (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)[C(Me)₂CH₂NH₂] (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe]₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)[(3S)-3-(OH)-Pyd-1-yl] (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)[(2R)-2-(HOCH₂)-Pyd-1-yl] (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)[4-(OH)-Pid-1-yl] (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)[(3R)-3-(OH)-Pid-1-yl] (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)N(Et)₂ (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)[(3S)-3-(OH)-Pyd-1-yl] (R)Pyd-2-CH₂ H 4-F-Bn R 2 2 c-Hex C(O)[(2R)-2-(HOCH₂)-Pyd-1-yl] (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex N(Me)[C(Me)₂CH₂OH] 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₃OH 1-Pyd-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)₂ 1-Pyd-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH 1-Pyd-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ 1-Pyd-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe 1-Pyd-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH 1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F (R)-3-BnO-1-pyd-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F (S)-3-BnO-1-pyd-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (i-Pr)(Me)N—(CH₂)₂ H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F NH₂—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ (Me)NH—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)C(Me)₃ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,4-diF—Ph C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-F-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (2R,4S)-4F-Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)CH(Me)₂ (S)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,4-diF—Ph C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)N(Me)(CH₂)₂OH (R)Pyd-2-CH₂ H 4-Cl-Bn R 2 2 2,3-diF—Ph C(O)N(Me)(CH₂)₂OMe (R)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (S)-1-Me-Pid-3-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)-1-Me-Pid-3-CH₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pyd-3-yl H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (R)Pyd-3-yl H Bn R 2 2 c-Hex C(O)CH(Me)₂ (S)Pyd-3-yl H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ (S)Pyd-3-yl H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OH (S)Pyd-3-yl H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH 2-oxo-1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH 2-oxo-1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH 3-OH-1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃F 3-OH-1-Pyd-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₃OH (i-Pr)HN—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)₂ (i-Pr)HN—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (i-Pr)HN—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ (i-Pr)HN—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe (i-Pr)HN—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)₂ (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(c-Pr)(CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(i-Pr)(CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OMe](CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OH]₂ (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Me)(CH₂)₂OMe (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OMe (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₃F (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂F (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₃OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OMe](CH₂)₃OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(Et)₂ (S)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(i-Pr)(CH₂)₂OH (S)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N[(CH₂)₂OH]₂ (S)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OMe (S)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(Et)(CH₂)₃OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)₂ (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(c-Pr)(CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(i-Pr)(CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OMe](CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OH]₂ (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Me)(CH₂)₂OMe (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OMe (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₃F (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂F (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₃OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OMe](CH₂)₃OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(Et)₂ (R)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(i-Pr)(CH₂)₂OH (R)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N[(CH₂)₂OH]₂ (R)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OMe (R)-3-OH-Pyd-1-(CH₂)₂ H 4-F-Bn R 2 2 c-Hex N(Et)(CH₂)₃OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Et)₂ 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(c-Pr)(CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(i-Pr)(CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OMe](CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OH]₂ 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Me)(CH₂)₂OMe 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OMe 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₃F 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂F 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N(Et)(CH₂)₃OH 2-oxo-1-pyd--(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex N[(CH₂)₂OMe](CH₂)₃OH 2-oxo-1-pyd--(CH₂)₂— H 4-F-Bn R 2 2 c-Hex N(Et)₂ 2-oxo-1-pyd--(CH₂)₂— H 4-F-Bn R 2 2 c-Hex N(Et)(CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-F-Bn R 2 2 c-Hex N(i-Pr)(CH₂)₂OH 2-oxo-1-pyd--(CH₂)₂— H 4-F-Bn R 2 2 c-Hex N[(CH₂)₂OH]₂ 2-oxo-1-pyd--(CH₂)₂— H 4-F-Bn R 2 2 c-Hex N[(CH₂)₂F](CH₂)₂OMe 2-oxo-1-pyd--(CH₂)₂— H 4-F-Bn R 2 2 c-Hex N(Et)(CH₂)₃OH Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(c-Pr)(CH₂)₂OH Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C O)N[(CH₂)₂OMe]₂ Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂OMe Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OMe Mor-(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F Mor-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂OH Mor-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH Mor-(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OH]₂ NH₂—(CH₂)₂ H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)CH(Me)₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)OMe (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂—OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂—OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OH]₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OMe]₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)[(2R)-2-(HOCH₂)-Pyd-1-yl] (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)(4-amino-Pid-1-yl) (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂—OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Me)(CH₂)₂—OMe (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)₂ (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F (Me)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Me)OMe (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂—OH (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂—OH (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OH]₂ (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OMe]₂ (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F (Me)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂—OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂—OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OH]₂ (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OMe]₂ (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N[(CH₂)₂F](CH₂)₂OH (Et)₂N—(CH₂)₂— H 4-Cl-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂F (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₃OH (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(Et)(CH₂)₂—OH (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(n-Pr)(CH₂)₂—OH (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OH]₂ (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂—OMe]₂ (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N(i-Pr)(CH₂)₂OH (Et)₂N—(CH₂)₂— H 4-F-Bn R 2 2 c-Hex C(O)N[(CH₂)₂OMe](CH₂)₂OH H H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ H H 4-Cl-Bn R 1 1 c-Hex C(O)C(Me)₃ H H 4-Cl-Bn R 1 1 c-Hex C(O)OMe H H 4-Cl-Bn R 1 1 c-Hex C(O)N(Me)₂ H H 4-Cl-Bn R 1 1 c-Hex S(O)₂Me H H 4-Cl-Bn R 1 1 c-Pen C(O)CH(Me)₂ H H 4-Cl-Bn R 1 1 c-Hep C(O)CH(Me)₂ H H 4-Cl-Bn R 1 1 i-Pr C(O)CH(Me)₂ H H 4-Cl-Bn R 1 1 (c-Hex)Me C(O)CH(Me)₂ H H 4-Cl-Bn R 1 1 2-Me-(c-Hex) C(O)CH(Me)₂ H H 4-Cl-Bn R 1 1 i-Bu C(O)CH(Me)₂ MeO₂C—CH₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ HO₂C—CH₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ Gly H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ N-diMe-Gly H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (S)His H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ N-BOC-(S)His H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (R)Pro H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ N-Me-(R)Pro H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (S)Pro H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (R)Pid-2-CO H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ N—Me-(R)Pid-2-CO H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (R)Tic H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (R)Pyd-2-CH₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ Pyd-1-(CH₂)₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (R)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (Me)₂N—(CH₂)₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (R)-Pid-2-CH₂ H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂ (Me)₂N—(CH₂)₂ H 4-Cl-Bn R 1 1 c-Hex C(O)C(Me)₃

H 4-Cl-Bn R 1 1 c-Hex C(O)CH(Me)₂

The compounds according to the present invention also can form pharmaceutically acceptable salts. These pharmaceutically acceptable salts include acid forming non-toxic acid addition salt containing pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; organic carboxylic acid such as tartaric, formic, citric, acetic, trichloroacetic, trifluoroacetic, gluconic, benzoic, lactic, fumaric, maleic, and the like; acid-addition salts formed by sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, and the like; preferably, acid-addition salts formed by sulfuric acid, methansulfonic acid or hydrohalic acid, and the like. The compounds of formula 1 according to the present invention can be converted to its salts by customary method.

Also, the compounds according to the present invention can have asymmetric carbon center, and so can be present as R or S isomeric forms, racemates, diastereomeric mixtures, and individual diasteromers. The present invention encompasses all these isomeric forms and mixtures.

The compounds according to the present invention can be prepared according to the procedures explained in the following Schemes 1-9. In the following Schemes, compounds of general formula (3), (6), (11), (12), (13), (14), (17), (18), (22), (24), (40) and (43) represent representative compounds of formula 1.

Compounds of formula (3) can be prepared by coupling protected amino acids (1) (P represents protecting groups, such as BOC, Cbz, Fmoc, etc.) with substituted amino-cyclic amine derivatives (2) (cyclic amine represent pyrrolidine, piperidine, or azetidine) under standard peptide coupling conditions, as illustrated in Scheme 1. The protected amino acids (1), starting materials, are either commercially available or may be prepared by known methods (Williams, R. M., Synthesis of Optically Active a-Amino Acids, Pergamon Press: Oxford, 1989). Similarly, the amino-cyclic amine derivatives (2) can be prepared following literature methods described for analogous compounds.

Compounds of formula (6) may be prepared by coupling N-substituted amino acid derivatives (5) with amino-cyclic amine derivatives (2), as illustrated in Scheme 2. Alkyl, acyl, or sulfonyl substituted amino acid derivatives (5) can be converted to amino acid derivatives (6) by hydrolysis in the presence of base.

Compounds of formula (10), (11), (12), and (14) may be prepared by coupling protected amino acid derivatives (7), (8), (9), and (10) with the compounds of formula (3) as shown in Scheme 3 [Cy in compound (8) represents pyrrolidine, azetidine, aziridine, piperidine, etc.]. Protected amino acid derivatives (7), (8) and (9) are either commercially available or can be prepared by general protection reaction from various amino acids.

In the above Reaction Scheme 3, R^(6′) is same as defined above in R⁶, and R represents alkyl or protected aminoalkyl.

Alkylated amine compounds of formula (17) or (18) can be prepared through reductive amination of protected amino aldehydes of formula (15) with compounds of formula (3) prepared in Scheme 1, as shown in Scheme 4. As a reducing agent in the reductive amination, NaHB(OAc)₃ or NaBH₃CN may be used, and DCE, DMF, methanol, DCM, etc. may be used as a solvent, but the reaction reagents and solvents are not limited to these. The protected amino aldehydes (15) is either commercially available or can be prepared by known methods such as reduction of thioesters or oxidation of amino alcohols. Compounds of formula (16) are general alkyl aldehydes, amino aldehydes or hydroxy aldehydes whose amino or alcohol group is either substituted or protected. These compounds are either commercially available or can be prepared by protection reaction. Mono- or di-substituted compounds (18) can be prepared by reductive amination and deprotection.

Compounds of formula (22), (23) and (24) can be prepared as shown in the following Scheme 5. Nitrobenzenesulfonyl protected intermediates of formula (19) can be converted to the compounds of formula (21) by alkylation or reductive amination (Tetrahedron Lett., 1995, 36, 6373-6374). In compounds of formula (20) such as dimethylaminoethylchloride or N-BOC-2-aminoethyl-chloride, Q represents aminoalkyl or alkylated aminoalkyl, and X represents halogen. Compounds of formula (23) can be prepared through reductive amination of compounds of formula (21) and then converted into the compounds of formula (24) by alkylation.

3-Disubstituted amino pyrrolidine derivatives (30) can be prepared as illustrated in Scheme 6. Compound (26) prepared from the commercially available compound (25) can be converted to compounds of formula (28) by reductive amination. Compounds of formula (30) can be prepared by acylation, amide coupling, or alkylation of compounds formula (28), and removing cbz group. Compounds of formula (30) can also be prepared from compound (31) using the similar method illustrated in Scheme 7.

In the above reaction scheme, compound (29) represents alkylhalide, substituted alkylhalide, carboxylic acid, or acid chloride; and R⁶ is the same as defined above; and X represents OH, Br, Cl, etc.

4-Disubstituted piperidine derivatives (35) can be prepared as illustrated in Scheme 7. Compounds of formula (34) can be prepared by introducing various amine groups into compound (32) by reductive amination. Amino piperidine derivatives (35) can be prepared by acylation, amide coupling reaction, or akylation of compounds of formula (34), and deprotection.

Azetidine derivatives can be prepared by the method illustrated in Scheme 8. Coupling of protected amino acid derivatives (1) with 3-azetidinol gives compounds of formula (37) which can then be converted into carbonyl compounds of formula (38). Compounds of formula (40) can be prepared from compounds of formula (38) via reductive amination, acylation, amide coupling, and alkylation.

Urea derivatives can be prepared by the method illustrated in Scheme 9. Coupling of protected amino acid derivatives (1) with cyclic amine derivatives (41) produces compounds of formula (42). Compounds of formula (42) can be converted to urea derivatives (43) by phosgene-mediated amide coupling.

In the above reaction scheme, NRR′ represents substituted or unsubstituted amino group among the definition of R⁷, R⁸, or R⁹.

It is preferable to carry out each step of the above methods in conventional solvents which do not have significant deleterious effect to the reaction, and particularly preferable to use one or more kinds selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, and chloroform.

Deprotection reaction can be carried out in the presence of strong acid such as hydrochloric acid, trifluoroacetic acid, etc., in the presence of amine base such as triethylamine, diisopropylethylamine, etc., or by hydrogenation. Specific reaction conditions are described in T. W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp 309-405.

Known coupling agents usable in coupling reaction are, but are not limited to, carbodiimides such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,1′-dicarbonyldiimidazole (CDI), etc. which are used in a mixture with 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT); bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP—Cl), diphenylphosphorylazide (DPPA), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), etc.

General separation of mixtures is conducted by column chromatography, and in case of final compound, separation can be done by recrystallization or normal or reverse HPLC (Waters, Delta Pack, 300×50 mm I.D., C18 5 μm, 100 A). When recrystallization or HPLC is used for purification, the compound can be obtained in the form of trifluoroacetic acid salt. Hydrochloric acid salt can be obtained by using ion exchange resin.

After the above reactions according to the present invention are completed, products can be separated and purified by customary work-up methods, for example, chromatography, recrystallization, etc.

The compounds of the present invention have potent agonistic effect against melanocortin receptors, and so the present invention provides a melanocortin receptor agonistic composition comprising the compound of formula 1 as active ingredients together with pharmaceutically acceptable carrier. In particular, the composition according to the present invention has potent effect for the prevention and treatment of, but not limited to, diabetes, erectile dysfunction, obesity, and inflammation.

When the compounds according to the present invention are administered for clinical purpose, a preferable daily dose would be within the range of 0.01˜10 mg/kg body weight as unitary dosage or separated dosage. However, a dosage level specific to individual patients can be varied, depending upon specific compound to be used, weight, sex, health condition, diet, administration time and method of drug, excretion rate, drug mixing, and severity of disease condition.

Any route depending on purpose can administer the compounds according to the present invention. Injection, and oral and nasal administration are preferred, but administration may be made through dermal, intraperitoneal, retroperitoneal, and rectal route.

Injectable preparation, for example, aqueous or oily suspension for sterile injection, can be prepared according to known method by using proper dispersants, wetting agents, or suspending agents. Solvents usable for this purpose are water, ringer's solution, and isotonic NaCl solution, and sterilized fixed oil is conventionally used as solvent or suspending media, too. Any non-irritable fixed oil including mono-, di-glyceride can be used for this purpose, and aliphatic acid such as oleic acid can be used for injectable preparation.

Solid dosage forms for oral administrations are capsules, tablets, pills, powders and granules, and in particular, capsules and tablets are useful. Capsules and tablets are preferable to be prepared as enteric coating. Solid dosage forms can be prepared by mixing compound (1) according to the present invention with one or more inert diluents such as sucrose, lactose, starch, etc., and carriers, for example, lubricants like magnesium stearate, disintegrants, binding agents, etc.

Abbreviations used in the above Description, and the following Preparations and Examples are as follows:

-   Ac acetyl -   Bn benzyl -   Bu butyl -   CBZ(Cbz) benzyloxycarbonyl -   BOC(Boc) tert-butoxycarbonyl -   Fmoc 9-fluorenylmethoxycarbonyl -   c-Hep cycloheptyl -   c-Hex cyclohexyl -   c-Pr: cyclopropyl -   c-Pen cyclopentyl -   DAST Diethylaminosulfur trifluoride -   DCC dicyclohexylcarbodiimide -   DCE dichloroethane -   DCM dichloromethane -   DEAD diethylazodicarboxylate -   Dic decahydroisoquioline-3-carboxylic acid -   DIPEA diisopropylethylamine -   DMAP 4-dimethylaminopyridine -   DMF N,N-dinethylformamide -   DMSO Dimethylsulfoxide -   DTic (D)-1,2,3,4-tetrahydriosoquinoline-3-carboxylic -   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl -   Gly Glycine -   Hex hexane -   HOBt 1-hydroxybenzotriazole -   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium -   hexafluorophosphate -   i-Bu isobutyl -   i-Pr isopropyl -   Mor Morpholine -   MOM Methoxymethyl -   Nos 2-Nitrobenzene sulfonyl -   Ph phenyl -   Phe phenylalanine -   Pid piperidine -   Pro proline -   Pyd pyrrolidine -   TEA triethylamine -   TFA trifluoroacetic acid -   TH:F Tetrahydrofuran -   Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

The following Intermediates further illustrate preparation of intermediates needed for synthesis of the compounds according to the present invention.

Intermediate 1: (3S)-1-Cbz-3-aminopyrrolidine Step A: (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine

To a solution of (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine (5.00 g, 26.9 mmol) and TEA (7.54 mL, 53.8 mmol) in DCM (6 mL) was added CbzCl (5.50 g, 29.6 mmol) at rt. After 4 h, a saturated aqueous NH₄Cl solution was added and the reaction mixture was extracted with DCM followed by EtOAc. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc/Hex=1/2) to give the title compound (9.06 g, 96.1%).

MS [M+H]=321 (M+1)

Step B: (3S)-1-Cbz-3-amino-pyrrolidine

The product of Step A, (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine, (5.26 g, 16.4 mmol) was dissolved in EtOAc (50 mL) and treated with a saturated HCl in EtOAc (15 mL). After the reaction mixture was stirred at rt for 30 min., the volatiles were removed to provide the title compound (4.11 g, 98.1%) as a colorless solid. The crude product was used without further purification.

MS [M+1]=221 (M+1)

Intermediate 2: (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine

To a solution of (3S)-1-Cbz-3-aminopyrrolidine (4.11 g, 16.0 mmol) and cyclohexanone (2.36 g, 24.0 mmol) in DCE (50 mL) was slowly added NaBH(OAc)₃ (6.78 g, 32.0 mmol) at rt. The reaction mixture was quenched after 4 h using a saturated aqueous NaHCO₃ solution and extracted with DCM followed by EtOAc. The combined organic extracts were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc/Hex=2/1) to give the title compound (4.79 g, 98.1%).

MS [M+1]=303 (M+1)

Intermediate 3: 4,4-Dimethyl-cyclohexan-1-one

4,4-Dimethyl-cyclohexene-1-one (5 g, 52 mmol) and n-pentane (50 mL) were placed in a hydrogen reaction vessel and Pd/C (300 mg) was added. The hydrogen reaction vessel was purged three times with hydrogen and subsequently pressurized with hydrogen (25 psi). After shaking in a Parr hydrogenator for 30 min., the reaction mixture was filtered though Celite and the filtrate concentrated in vacuo to give the title compound.

MS[M+H]=127 (M+1)

Intermediate 4: 1-BOC-4-piperidone

To a solution of 4-piperidone (10 g, 100 mmol) and TEA (28.0 mL, 20 mmol) in DCM (2.00 l) was added di-t-butyldicarbonate (30 g, 150 mmol) at rt. After 4 h, the reaction mixture was concentrated in vacuo and the residue was diluted with 1N HCl (500 mL). The reaction mixture was extracted with EtOAc, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/15) to give the title compound (19.1 g, 96.5%).

MS[M+H]=200 (M+1)

Intermediate 5: Spiro[2,5]octanone Step A: 4,4-Methylene-1,1-ethyleneketal-4-spiro[2,5]octane

To a solution of DMSO (80 mL), filled with nitrogen, was added NaH (2.3 g, 58 mmol), and the reaction mixture was heated at 50-60° C. When the reaction solution turned light green, MeP (Ph)₃Br (21.2 g, 60 mmol) was added, and the reaction solution was cooled to rt and stirred for 1 h. Cyclohexanedione monoethyleneketal (5.64 g, 36 mmol) was slowly added, and then the reaction mixture was heated to 40° C. and stirred for additional 2 h. The reaction solution was cooled to rt and a solution of diethyl ether/ice-water was added. The organic solution extracted with Et₂O was dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/5) to give the title compound (4.51 g, 82%).

MS[M+H]=155 (M+1)

Step B: spiro[2,5]octanone

To a solution of 4,4-methylene-1,1-ethyleneketal-4-spiro[2,5]octane (4.5 g, 30 mmol), prepared by Step A, in Et₂O was added CH₂I₂ (12.0 mL, 150 mmol) and Zn—Cu (12.3 g, 48 mmol). The mixture was stirred at rt for 12 h, filtered, and diluted with 1N HCl solution. The organic material was extracted with diethyl ether, dried over MgSO₄ and then concentrated in vacuo to give the title compound. The crude product was used without further purification.

Intermediates 6˜35

The compounds below were prepared following the procedure described in Intermediate 2 using commercially available amines, carbonyl compounds, amine compound prepared in Intermediate 1, and carbonyl compounds prepared in Intermediates 4, and 5.

Intermediate P n R⁴ * MS (M + 1) 6 BOC 1 c-Hex S 303 7 Cbz 1 c-Hex R 303 8 Cbz 1 c-Pen S 289 9 Cbz 1 c-Hep S 317 10 Cbz 1 i-Pr S 263 11 Cbz 1 (c-Hex)-CH₂— S 317 12 Cbz 1 Ph R,S 297 13 Cbz 1 4-Me—Ph R,S 311 14 Cbz 1 3,5-diMe—Ph R,S 325 15 Cbz 1 2-Adamantyl S 355 16 Cbz 1 4-cis-Me-(c-Hex) S 317 17 Cbz 1 4-trans-Me-(c-Hex) S 317 18 Cbz 1 4,4-di-Me-(c-Hex) S 331 19 Cbz 1 4-t-Bu-(c-Hex) S 359 20 Cbz 1 4-cis-Et-(c-Hex) S 331 21 Cbz 1 4-trans-Et-(c-Hex) S 331 22 Cbz 1 N—BOC-Pip-4-yl S 404 23 Cbz 1 4,4-ethyleneketal-(c-Hex) S 361 24 Cbz 1 Spiro[2,5]octan-1-yl S 329 25 Cbz 1 4-Ph-c-Hex S 379 26 BOC 2 c-Hex 283 27 BOC 2 c-Pen 269 28 BOC 2 c-Hep 297 29 BOC 2 i-Pr 243 30 BOC 2 (c-Hex)-CH₂— 297 31 BOC 2 i-Bu 257 32 BOC 2 2-Me-c-Hex 297 33 BOC 2 4,4-diMe-c-Hex 311 34 BOC 2 4-trans-Me-c-Hex 297 35 BOC 2 4-cis-Me-c-Hex 297

Intermediate 36: (3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine Step A: (3S)-1-Cbz-3-[cyclohexyl(isobutyryl)amino]pyrrolidine

To a solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrolidine (4.75 g, 15.1 mmol) and TEA (4.26 mL, 30.2 mmol) in DCM (50 mL) was added dropwise isobutyryl chloride (1.15 mL, 60.3 mmol). The reaction mixture was stirred at rt for 12 h and quenched with 1N HCl solution. The organic material was extracted with DCM (50 mL×2) followed by EtOAc (50 mL×2), and the extracts were washed with a saline, dried over MgSO₄, and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (5.40 g, 96.7%).

MS[M+H]=372 (M+1)

Step B; (3)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine

To a solution of (3S)-1-cbz-3-[cyclohexyl(isobutyryl)amino]pyrrolidine (5.00 g, 13.4 mmol), prepared in Step A, in Dioxane (40 mL) was added dropwise Pd/C (250 mg) at rt. After 12 h, the reaction mixture was filtered though Celite and the filtrate concentrated in vacuo to give the title compound as an oil (3.14 g, 98.5%).

MS[M+H]=239 (M+1)

Intermediates 37-61

The compounds below were prepared following the procedure described in Intermediate 36 or a step B of Intermediate 1 using acylchlorides or carbonyl compounds.

Intermediates * n R⁴ R⁵ MS (M + 1) 37 S 1 C(O)C(Me)₃ c-Hex 253 38 S 1 C(O)Me c-Hex 227 39 S 1 S(O)₂Me c-Hex 247 40 S 1 C(O)N(Me)₂ c-Hex 240 41 S 1 C(O)CH(Me)₂ c-Pen 225 42 S 1 C(O)CH(Me)₂ c-Hep 253 43 S 1 C(O)CH(Me)₂ i-Pr 199 44 S 1 C(O)CH(Me)₂ (c-Hex)-CH₂— 253 45 R 1 C(O)CH(Me)₂ c-Hex 238 46 R 1 C(O)C(Me)₃ c-Hex 253 47 R 1 C(O)N(Me)₂ c-Hex 240 48 R 1 C(O)CH(Me)₂ c-Pen 225 49 2 C(O)CH(Me)₂ c-Hex 253 50 2 C(O)C(Me)₃ c-Hex 267 51 2 C(O)OMe c-Hex 241 52 2 S(O)₂Me c-Hex 261 53 2 C(O)N(Me)₂ c-Hex 254 54 2 Et c-Hex 210 55 2 i-Bu c-Hex 238 56 2 C(O)CH(Me)₂ c-Pen 239 57 2 C(O)CH(Me)₂ c-Hep 267 58 2 C(O)CH(Me)₂ i-Pr 212 59 2 C(O)CH(Me)₂ (c-Hex)-CH₂— 267 60 2 C(O)CH(Me)₂ i-Bu 226 61 2 C(O)N(Me)₂ 2-Me-c-Hex 267

Intermediate 62: (3S)-1-benzyl-3-[(2,4-difluorophenyl)amino]pyrrolidine

To a solution of (3S)-1-benzyl-3-aminopyrrolidine (0.20 g, 1.1 mmol), tris-(2,4-difluorophenyl)bismuth (0.64 g, 1.2 mmol), and TEA (0.280 mL, 2 mmol) in DCM (5 mL) was added Cu(OAc)₂ (0.21 g, 1.2 mmol). After being stirred at rt for 24 h, the reaction solution was concentrated in vacuo, and the residue was purified by column chomatography (MeOH/CHCl₃=1/25) to give the title compound (150 mg, 46.0%).

MS[M+H]=289 (M+1)

Intermediate 63: (3S)-1-benzyl-3-[isobutyryl(2,4-difluorophenyl)amino]pyrrolidine

To a solution of (3S)-1-benzyl-3-[(2,4-difluorophenyl)amino]pyrrolidine (150 mg, 0.52 mmol) and DMAP (6 mg, 0.05 mmol) in pyridine (7 mL) was added isobutyryl chloride (0.16 mL, 1.5 mmol) at 0° C. After being stirred at 60° C. for 18 h, the reaction mixture was quenched with an aqueous NaH(CO)₃ solution and extracted with EtOAc. The extracts were concentrated in vacuo, the reside was purified by column chomatography (MeOH/CHCl₃=1/25) to give the title compound (160 mg, 86.0%).

MS[M+H]=359 (M+1)

Intermediate 64: (3S)-3-[(isobutyryl(2,4-difluorophenyl)amino)pyrrolidine

To a solution of (3S)-1-benzyl-3-[isobutyryl(2,4-difluorophenyl)amino]pyrrolidine in 1N HCl and an aqueous EtOH solution was added Pd/C, and the reaction mixture was stirred at rt for 3 days under hydrogen. The reaction mixture was filtered though Celite, and the filtrate concentrated in vacuo. The crude product was recrystalized from EtOAc to give the title compound (99 mg, 73%) as a colorless prism.

MS[M+H]=269 (M+1)

Intermediate 65: (3S)-3-[(isobutyryl(2,5-difluorophenyl)amino)pyrrolidine

The title compound was prepared following the procedure described in Intermediates 63 and 64 using (3S)-1-benzyl-3-[(2,5-difluorophenyl)amino]pyrrolidine.

MS[M+H]=269 (M+1)

Intermediate 66: (3S)-3-[(isobutyryl(3,4-difluorophenyl)amino)pyrrolidine

The title compound was prepared following the procedure described in Intermediates 63 and 64 using (3S)-1-benzyl-3-[(3,4-difluorophenyl)amino]pyrrolidine.

MS[M+H]=269 (M+1)

Intermediate 67: 1-hydroxymethyl-1-cyclopentanecarboxylic acid

Cyclopentanecarboxylic acid (1.10 g, 10.0 mmol) was placed in a round-bottomed bottomed flask, filled with nitrogen, and 30 mL of THF (30 mL) was added. The solution was cooled to −78° C., and LDA (8.8 mL, 2.5 m in hexane) was added dropwise. After being stirred for 30 min., the solution was bubbled by nitrogen stream containing formaldehyde gas (formaldehyde gas was in situ generated by thermal degradation of anhydrouse paraformaldehyde at 160° C.). When the reaction solution turned light yellow, the reaction mixture was quenched with a saturated aqueous NH₄Cl solution at −78° C., and the organic material was extracted with EtOAc. The organic extracts were dried over MgSO₄, filtered, and concentrated in vacuo to give the title compound.

MS[M+H]=145 (M+1)

Intermediate 68: 2,2-dimethyl-3-methoxypropionic acid Step A: 2,2-dimethyl-3-methoxypropionic acid ethyl ester

To a solution of 2,2-dimethyl-3-hydroxypropionic acid ethyl ester (1.3 g, 10.0 mmol) in CH₃CN (30 mL) was added Ag₂O (11.5 g, 50.0 mmol) and methyl iodide (0.56 mL, 11 mmol). The reaction mixture was stirred at rt for 12 h and quenched with a saturated aqueous NH₄Cl. The mixture was filtered though Celite, the filtrate concentrated in vacuo, and the residue was purified by column chromatography (EtOAc/Hex=1/10) to give the title compound (1.34 g, 91.2%).

MS[M+H]=147 (M+1)

Step B: 2,2-dimethyl-3-methoxypropionic acid

To a solution of 2,2-dimethyl-3-methoxypropionic acid ethyl ester (1.17 g, 8.00 mmol) in an aqueous MeOH solution (MeOH/H₂O=1/1, 24 mL) was added LiOH (560 mg, 16.0 mmol) at rt. After the rection mixture was stirred for 30 min., the solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer extracted with EtOAc, and the organic extracts were dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was used without further purification.

MS[M+H]=133 (M+1)

Intermediate 69: 2,2-dimethyl-3-benzyloxypropionic acid

The title compound was prepared following the procedure described in Intermediate 68 using 2,2-dimethyl-3-hydroxypropionic acid ethyl ester and benzyl chloride.

MS[M+H]=209 (M+1)

Intermediate 70: 1-BOC-piperidine-4-carboxylic acid

To a solution of piperidine-4-carboxylic acid (1.29 g, 10.0 mmol) in water was added NaOH (800 mg, 20.0 mmol). When the reaction solution was clear, (BOC)₂O (2.5 g, 11.0 mmol) was added, and the reaction mixture was stirred at rt for 12 h. The solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer was extracted with EtOAc, and the organic extracts were dried over MgSO₄, filtered, and concentrated in vacuo. The product was used without further purification.

MS[M+]=230 (+1)

Intermediate 71: (2R)-2-methyl-3-acetyloxypropionic acid

To a solution of (2R)-2-methyl-3-hydroxypropionic acid (10.0 g, 100 mmol) in pyridine (30 mL) as added acetyl chloride(11.8 g, 15.0 mmol) at 0° C., and the reaction mixture was warmed to rt. After being stirried for 3 h, the reaction mixture was quenched with 1N HCl (30 mL), and the pH of the solution was adjusted to 3-4. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl at 4-5 times, dried over MgSO₄, filtered, and concentrated to give the title compound (11.4 g, 95.0%).

MS[M+H]=147 (M+1)

Intermediates 72-80

The compounds below were prepared following the procedure described in Intermediate 71 using various hydroxy carboxylic acid compounds.

Intermediate R R′ R″ MS (M + 1) 72 Me Me OAc 147 73 Me Me CH₂OAc 161 74 Me Me (CH₂)₂OAc 175 75 Me Me (CH₂)₃OAc 189 76 Me CH₂—OAc CH₂OAc 218 77 —(CH₂)₃— CH₂OAc 187 78 —(CH₂)₂— CH₂OAc 159 79 2-(AcOCH₂)-1-cyclopenten-1-yl 185 80 2-(AcOCH₂)-1-cyclohexen-1-yl 199

Intermediate 81: (3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine Step A: 2,2-dimethyl-3-acetyloxypropionyl chloride

Intermediate 73, 2,2-dimethyl-3-acetyloxypropionic acid (11.76 g, 80 mmol) was dissolved in benzene (100 mL), and the reaction solution was cooled to 0° C. Oxalyl chloride (15.0 g, 120 mmol) was added dropwise. After being stirred for 3 h, the solvent was removed in vacuo, and the residue was distilled in vacuo to give the title compound.

MS[M+H]=179 (M+1)

Step B: (3S)-1-Cbz-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine

To the mixture of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (3.0 g, 10 mmol), TEA (15 mL), and DMAP (1.25 g, 10 mmol) in THF (15 mL) was added 2,2-dimethyl-3-acetyloxypropionyl chloride (3.58 g, 20 mmol) prepared in Step A. After the reaction mixture was refluxed for 48 h (90-110° C.), the solvent was removed, and the residue was diluted with an aqueous NaHCO₃ solution was added to the residue. The organic material was extracted with EtOAc, and the extracts were washed by 1N HCl, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (2.80 g, 62.9%).

MS[M+H]=445 (M+1)

Step C: (3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine

To a solution of (3S)-1-Cbz-3-[cyclohexyl (acetyloxypivaloyl)amino]pyrrolidine (1.00 g, 2.25 mmol), prepared in Step B, in dioxane (10 mL) was added portionwise Pd/C (200 mg), and the mixture was stirred for 12 h under hydrogen. The reaction solution was filtered though Celite and the filtratae concentrated to give the title compound (657 mg, 84%).

MS[M+H]=311 (M+1)

Intermediates 82-125

The compounds below were prepared following the procedure described in Intermediate 81 or Step B of Intermediate 1 using commercially available carboxylic acid or carboxylic acid prepared in Intermediates 67-80, and amine compounds prepared in Intermediates 2, 6 and 6˜35.

Intermediate n * R R′ R″ R⁴ MS (M + 1) 82 1 S H OH i-Pr c-Hex 311 83 1 S H H C(Me)₂OH c-Hex 269 84 1 S H Me CH₂—OAc c-Hex 297 85 1 S Me Me OAc c-Hex 297 86 1 S Me Me (CH₂)₂—OAc c-Hex 325 87 1 S Me Me (CH₂)₃—OAc c-Hex 339 88 1 S Me Me CH₂—OAc 4-cis-Me-c-Hex 325 89 1 S Me Me CH₂—OAc 4-trans-Me-(c-Hex) 325 90 1 S Me Me CH₂—OAc 4,4-di-Me-(c-Hex) 339 91 1 S Me Me CH₂—OAc 4-t-Bu-(c-Hex) 367 92 1 S Me Me CH₂—OAc 4-cis-Et-(c-Hex) 339 93 1 S Me Me CH₂—OAc 4-trans-Et-(c-Hex) 339 94 1 S Me Me CH₂—OAc Spiro[2.5]octan-1-yl 337 95 1 S Me Me CH₂—OAc 4-Ph-c-Hex 387 96 1 S Me Me CH₂—OAc

369 97 1 S Me CH₂—OAc CH₂—OAc 4-cis-Me-(c-Hex) 383 98 1 S Me CH₂—OAc CH₂—OAc 4-trans-Me-(c-Hex) 383 99 1 S Me CH₂—OAc CH₂—OAc 4,4-di-Me-(c-Hex) 397 100 1 S Me CH₂—OAc CH₂—OAc c-Hex 369 101 1 S Me Me CH₂—OMe c-Hex 283 102 S Me Me CH₂—OBn c-Hex 359 103 1 S Me Me (CH₂)₃—O-(2,4-diMe)Ph c-Hex 401 104 1 S —(CH₂)₄— CH₂—OAc c-Hex 337 105 1 S —(CH₂)₂— CH₂—OAc c-Hex 309 106 1 S —(CH₂)₂— CO₂Et c-Hex 309 107 1 S H 1-BOC-Pid-4-yl c-Hex 380 108 1 S H 1-(Nos)-Pid-4-yl c-Hex 465 109 1 S 3-OH—Ph c-Hex 289 110 1 S 2-(AcOCH₂)-1-cyclopenten-1-yl c-Hex 335 111 1 S 2-(AcOCH₂)-1-cyclohexen-1-yl c-Hex 349 112 1 R Me Me CH₂—OAc c-Hex 311 113 1 R,S Me Me CH₂—OAc c-Hex 311 114 1 S Me Me CH₂—OAc 2,3-diF—Ph 341 115 1 R,S Me Me CH₂—OAc 2,3-diF—Ph 341 116 1 R,S Me Me CH₂—OAc 3,5-diMe-ph 333 117 1 R,S Me Me CH₂—OAc 4-Me—Ph 319 118 1 R,S Me Me CH₂—OAc Ph 305 119 1 S Me Me CH₂—OAc 2-Adamantyl 363 120 2 S Me CH₂—OAc CH₂—OAc 4-cis-Me-(c-Hex) 397 121 2 S Me CH₂—OAc CH₂—OAc 4-trans-Me-(c-Hex) 397 122 2 S Me CH₂—OAc CH₂—OAc 4,4-di-Me-(c-Hex) 411 123 2 S Me Me CH₂—OAc c-Hex 325 124 2 S 2-(AcOCH₂)-1-cyclopenten-1-yl c-Hex 349 125 2 S 2-(AcOCH₂)-1-cyclohexen-1-y1 c-Hex 363

Intermediate 126: (3S)-3-[acetyloxypivaloyl(4,4-diF-cyclohexyl)amino]pyrrolidine Step A: (3S)-1-cbz-3-[acetyloxypivaloyl (4-oxo-cyclohexyl)amino]pyrrolidine

Intermediate 96, (3S)-1-cbz-3-[acetyloxypivaloyl(4,4-ethyleneketal-cyclohexyl)amino]pyrrolidine (1.86 g, 5.16 mmol) was dissolved in THF (5 mL), and 3N HCl (5 mL) was added. The reaction solution was stirred at 50° C. for 12 h and neutralized by addition of a saturated aqueous 1N NaOH solution. The organic material was extracted with EtOAc and the extracts were dried over MgSO₄, concentrated in vacuo, and purified by column chomatography (EtOAc/Hex=1/1) to give the title compound (1.40 g, 85.7%).

MS[M+H]=459 (M+1)

Step B: (3)-1-cbz-3-[acetyloxypivaloyl(4,4-difluoro-cyclohexyl)amino]pyrrolidine

The product of Step A, (3S)-1-cbz-3-[acetyloxypivaloyl(4-oxo-cyclohexyl)amino]pyrrolidine (1.40 g, 4.42 mmol) was dissolved in DCM (15 mL), and DAST (1.42 g, 8.84 mmol) was added at −78° C., and the reaction mixture was warmed to rt. After being stirred for 24 h, the reaction mixture was quenched with a saturated aquenous NaHCO₃ solution w and extracted with DCM. The extracts were dried over MgSO₄ and concentrated in vacuo, and the residue purified by column chomatography (EtOAc/Hex=2/1) to give the title compound (500 mg, 33.5%).

MS[M+H]=481 (N+1)

Step C: 3-[acetyloxypivaloyl(4,4-diF-cyclohexyl)amino]pyrrolidine

The title compound was prepared following the procedure described in Intermediate 64 using the product of Step B, (3S)-1-cbz-3-[acetyloxypivaloyl (4,4-diF-cyclohexyl)amino]pyrrolidine.

MS[M+1]=347 (M+1)

Intermediate 127: (3S)-3-[acetyloxypivaloyl(4-F-cyclohexyl)amino]pyrrolidine Step A: (3S)-1-cbz-3-[acetyloxypivaloyl(4-hydroxycyclohexyl)amino]pyrrolidine

The product of Step A of Intermediate 126, (3S)-1-cbz-3-[acetyloxypivaloyl (4-oxo-cyclohexyl)amino]pyrrolidine (1.60 g, 3.49 mmol) was dissolved in THF (15 mL), and NaBH₄ (172 mg, 4.19 mmol) was added at rt. After being stirred for 12 h, the reaction mixture was quenched with water, and the organic material was extracted with EtOAc. The extracts were dried over MgSO₄ and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/1) to give the title compound (1.481 mg, 92.1%).

MS[M+H]=461 (M+1)

Step B: (3S)-1-cbz-3-[acetyloxypivaloyl(4-fluorocyclohexyl)amino]pyrrolidine

The title compound was prepared following the procedure described in Step B of Intermediate 126 using the product of Step A, (3S)-1-cbz-3-[acetyloxypivaloyl(4-hydroxy-cyclohexyl)amino]pyrrolidine.

MS[M+H]=463 (+1)

Step C: (3S)-3-[acetyloxypivaloyl(4-fluorocyclohexyl)amino]pyrrolidine

The title compound was prepared following the procedure described in Intermediate 64 using the product of Step B, (3S)-1-cbz-3-[acetyloxypivaloyl(4-fluoro-cyclohexyl)amino]pyrrolidine.

MS[M+1]=329 (M+1)

Intermediate 128: methyl 2-[(3S)-3-pyrrolidinyl(cyclohexyl)amino]acetate Step A: methyl 2-[(3S)-1-Cbz-3-pyrolidinyl(cyclohexyl)amino]acetate

NaH (60% in mineral oil, 52.0 mg, 1.30 mmol) was placed in a round-bottom flask, filled with nitrogen, and then THF (10 mL) was added. A solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrrolidine (302 mg, 1.00 mmol) prepared in Intermediate 2 in THF was added dropwise at 0° C., and the reaction mixture was stirred for 30 min until no further gas evolution occurred, followed by slow addition of methyl bromoacetate. After 4 h, the reaction, mixture was quenched with water and extracted with EtOAc. The extracts were dried over MgSO₄ and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (227 mg, 90.0%).

MS[M+H]=375 (M+1)

Step B: methyl 2-[(3S)-3-pyrrolidinyl(cyclohexyl)amino]acetate

The title compound was prepared following the procedure described in Step B of Intermediate 3 using the product of Step A, methyl 2-[(3S)-1-Cbz-pyrrolidin-3-yl (cyclohexyl) amino]acetate.

MS[M+H]=241 (M+1)

Intermediate 129: (3S)-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine Step A: A: (3S)-1-Cbz-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine

To a solution of (3S)-1-Cbz-3-{cyclohexylamino}pyrrolidine (3.0 g, 10.0 mmol), prepared in Intermediate 2, in DMF (30 mL) were added DIPEA (3.50 mL, 20.0 mmol), HBTU (4.88 g, 13 mmol), BOC-Gly (1.92 g, 11 mmol). After the mixture was stirred at rt for 4 h, the solvent was removed in vacuo, and the residue was diluted with an aqueous NaHCO₃. The organic material was extracted with EtOAc, and the organic extracts were washed with 1N HCl, dried over MgSO₄, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (4.63 g, 92.0%).

MS[M+H]=474 (M+1)

Step B: (3S)-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine

The title compound was prepared following the procedure described in Step B of Intermediate 3 using the product of Step A, (3S)-1-Cbz-3-{cyclohexyl[(N-BOC)aminoacetyl]amino}pyrrolidine.

MS[M+H]=340 (M+1)

Intermediates 130˜134

The compounds below were prepared following the procedure described in Intermediate 36 or 129 using commercially available carboxylic acid and amine compounds prepared in Intermediates 6˜35.

Intermediate R MS (M + 1) 130 CH₂NH(BOC) 354 131 CH₂CH₂NH(BOC) 368 132 CH₂C(O)OMe 297 133 CH₂OH 255 134 (CH₂)₂—OC(O)—CF₃ 365

Intermediate 135: (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine Step A: (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methyl ester

To a solution of (2R)-4-chlorophenylalanine methylester (213 mg, 1.00 mmol) in DCM (5 mL) was added dropwise TEA (280 μl, 2.00 mmol) and then methanesulfonylchloride (100 μl, 1.3 mmol) at 0° C. After 30 min, the reaction mixture was quenched with water and extracted with DCM and EtOAc. The organic solution was washed with 1N HCl, dried over MgSO₄ and concentrated in vacuo, and the residue was purified by column chomatography (MeOH/CHCl₃=1/25) to give the title compound (280 mg, 96.1%).

MS[M+H]=292 (M+1)

Step B: (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine

To a solution of (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methylester, prepared in Step A, in water/methanol (5 mL, 1/1) was added portionwise LiOH (70.0 mg, 2.00 mmol). After being stirred at rt for 3 h, the reaction mixture was concentrated, and the residue was diluted with 1N HCl solution. The organic material was extracted with EtOAc, the extracts were concentrated in vacuo to give the title compound (179 mg, 94.3%).

MS[M+H]=277 (M+1)

Intermediate 136: (2R)-N-acetyl-(4-chlorobenzyl)alanine

The title compound was prepared following the procedure described in Intermediate 135 using anhydrous (2R)-4-chlorophenylalanine methylester.

MS[M+H]=278 (M+1)

Intermediate 137: (2R)-N-[(N,N-dimethyl)carbamoyl]-(4-chlorobenzyl)alanine

The title compound was prepared following the procedure described in Intermediate 135 using (2R)-4-chlorophenylalanine methylester and chlorodimethyl carbamate.

MS[M+H]=278 (M+1)

Intermediate 138: (2R)-N-BOC-prolinal Step A: (2R)-N-BOC-proline ethylthioester

To a solution of DCC (2.55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) in DCM was added dropwise a solution of (2R)-N-BOC-proline (3.00 g, 9.52 mmol) in DCM (30 mL). The reaction mixture was stirred at rt for 30 min, and filtered though Celite. The filtrate was dried over MgSO₄ and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/4) to give the title compound (2.34 g, 95.2%).

MS[M+H]=260 (M+1)

Step B: (2R)-N-BOC-prolinal

To a solution of (2R)-N-BOC-proline ethylthioester, prepared in Step A, in acetone were added dropwise triethylsilane (5.39 g, 46.3 mmol) and Pd/C (100 mg) at 0° C. When no further gas evolution occurred, the reaction mixture was warmed to rt and then stirred for additional 30 min. The reaction solution was filtered though Celite, the filtrate concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/2) to give the title compound (1.43 g, 93.2%).

MS[M+H]=200 (M+1)

Intermediate 138: (2R)-N-methylprolinal Step A: (2R)-N-methylproline methyl ester

(2R)-proline methylester (1.20 g, 10.0 mmol) was dissolve in DMF (30 mL), and formalin (37% in water, 1.12 mL, 15.0 mmol) and NaBH (OAc)₃ (4.20 g, 20.0 mmol) were added portionwise. After 12 h, the reaction material was concentrated in vacuo, and the residue was diluted with NaHCO₃ (30 mL). The organic material was extracted with EtOAc, and the organic extracts were dried over MgSO₄ and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=4/1) to give the title compound (1.33 g, 93.0%).

MS[M+H]=144 (M+1)

Step B: (2R)-N-methylprolinal

The title compound was prepared following the procedure described in Step of Intermediate 135 using methyl (2R)-N-methyl-proline methylester prepared in Step A.

MS[M+H]=114 (M+1)

Intermediates 140˜148

The compounds below were prepared following the procedure described in Intermediates 138 and 139 using various amino acid derivatives.

Intermediate X n * MS (M + 1) 140 Me 1 S 114 141 Ac 1 R 142 142 S(O)₂Me 1 R 178 143 C(O)N(Me)₂ 1 R 171 144 n-Bu 1 R 156 145 Me 2 S 128 146 Me 2 R 128 147 Ac 2 R 156 148 S(O)₂Me 2 R 192

Intermediate 149: 1-BOC-2-aziridinecarboxylic acid Step A: Methyl 1-benzyl-2-aziridinecarboxylate

To a solution of methyl 2,3-dibromopropionate (92.50 g, 10.0 mmol) and K₂CO₃ (4.10 g 30.0 mmol) in acetonitrile (30 mL) was added dropwise benzylamine (1.20 mL, 11 mmol). After being stirred at rt for 4 h, and the reaction mixture was quenched with a saturated aqueous NH₄Cl solution. The organic material was extracted with EtOAc, the extracts dried over MgSO₄, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex 2/1) to give the title compound (1.62 g, 85%).

MS[M+H]=192 (M+1)

Step b: Methyl 1-BOC-2-aziridine carboxylate

To a solution of methyl 1-benzyl-2-aziridinecarboxylate (1.00 g, 5.23 mmol) and di-t-butyl-dicarbonate (1.34 g, 5.75 mmol), prepared in Step A, in methanol (20 mL) was added portionwise Pd/C (300 mg). The mixture was stirred at rt under hydrogen for 24 h and filtered though Celite. The filtrate was concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=2/1) to give the title compound (985 mg, 91.0%).

MS[M+H]=202 (+1)

Step C: 1-BOC-aziridine-2-carboxylic acid

The title compound was prepared following the procedure described in Step B of Intermediate 135 using methyl 1-BOC-2-aziridinecarboxylate prepared in Step B.

MS[+H]=188 (M+1)

Intermediate 150: 1-BOC-aziridine-2-carboxaldehyde

The title compound was prepared following the procedure described in Intermediate 138 using 1-BOC-aziridine-2-carboxylic acid.

MS[M+H]=172(M+1)

Intermediate 151: 2-ethylamino-1-acetyloxyethane Step A: 2-(BOC)amino-1-acetyloxyethane

To a solution of 2-(BOC)aminoethanol (3.2 g, 20.0 mmol) in DCM (60 mL) were added TEA (5.6 mL, 40.0 mL) and acetyl chloride (3.36 mL, 30 mmol) at 0° C. After the reaction solution was stirred for 2 h, the solvent was removed, and the residue dissolved in water. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO₄, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/10) to give the title compound (3.2 g, 80%).

MS[M+H]=204(M+1)

Step B: 2-amino-1-acetyloxyethane

2-(BOC)amino-1-acetyloxyethane (3.00 g, 15.0 mmol), prepared in Step A, was dissolved in DCM (15.0 mL), and TFA (15.0 mL) was added. After being stirred 30 min, the reaction mixture was concentrated in vacuo to give the title compound. The product was used without further purification.

MS[M+H]=104(M+1)

Step C: 2-[(2-nitrobenzene)sulfonyl]amino-1-acetyloxyethane

To a solution of 2-amino-1-acetyloxyethane (1.00 g, 10.0 mmol), prepared in Step B (1.00 g, 10.0 mmol) and Et₃N (2.80 mL, 20 mmol) in DCM (30 mL) was added dropwise (2-nitrobenzene)sulfonyl chloride (2.43 g, 22 mmol). After being stirred at rt for 4 h, the reaction mixture was quenched with water and extracted with EtOAc. The extracts were washed with 1N HCl, dried over MgSO₄, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (2.72 g, 94.0%).

MS[M+1]=289(M+1)

Step D: 2-{ethyl[(2-nitrobenzene)sulfonyl]}amino-1-acetyloxyethane

To a solution of 2-[(2-nitrobenzene)sulfonyl]amino-1-acetyloxyethane prepared in Step C (1.45 g, 5.00 mmol) and P(Ph)₃ (1.3 g, 5 mmol) in THF (15 mL) were added ethanol (0.40 mL, 15 mmol) and DEAD (0.32 mL, 10.0 mmol). After being stirred for 12 h, the solvent was removed and the residue was purified by column chromatography (eluent: EtOAc/Hex=1/5) to give the title compound (1.40 g, 80%).

MS[M+1]=317(M+1)

Step E: 2-ethylyamino-1-acetyloxyethane

To a solution of 2-{ethyl[(2-nitrobenzene)sulfonyl]}amino-1-acetyloxyethane (634 mg, 2.00 mmol) prepared in Step D in DMF (10 mL) were added K₂CO₃ (540 mg, 4 mmol) and mercaptobenzene (330 mg, 1.5 mmol). The reaction mixture was stirred at rt for 1 h, concentrated in vacuo, and diluted with water. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO₄, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound.

MS[M+H]=132(M+1)

Intermediate 152-157

The compounds below were prepared following the procedure described in Intermediates 151 using commercially available aminoalcohol or (N-BOC)aminoethanol.

Intermediate R R′ R″ R′′′ MS (M + 1) 152 Pr Ac H H 146 153 Et Me H H 104 154 c-Pr Ac H H 144 155 CH₂CH₂OMe Ac H H 162 156 Me Ac Me Me 146 157 CH₂CH₂OMe Me H H 134

Intermediate 158: (2R)-2-(BOC)amino-N-{4-[cyclohexyl(hydroxyethylcarbamoyl)amino]piperidine-1-yl}-3-(4-chlorophenyl)propionamide Step A; 4-[cyclohexyl)amino]piperidine

The title compound was prepared following the procedure described in Step A of Intermediate 1 using 1-BOC-4-[(cyclohexyl)amino]piperidine prepared in Intermediate 26.

MS[M+H]=183(M+1)

Step B; (2R)-2-(BOC)amino-N-[4-(cyclohexylamino)piperidine-1-yl]-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Intermediate 129 using (2R)-2-(BOC)amino-3-(4-chlorophenyl)propionic acid and 4-[(cyclohexyl)amino]piperidine.

MS[M+H]=464(M+1)

Step C: N-cyclohexyl[(2R)-2-(BOC)amino-3-(4-chlorophenyl)-1-oxo]piperidine-4-yl}carbamoyl chloride

To a solution of (2R)-2-(BOC)amino-N-[4-(cyclohexylamino)poperidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Step B (4.63 g, 10 mmol) in DCM (30 mL) was added phosgene (25% in toluene, 12.6 mL, 30 mmol). After the reaction solution was stirred at rt for 4 h, the solvent was removed, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (4.58 g, 87%).

MS[M+H]=526(M+1)

Step D: (2R)-2-(BOC)amino-N-{(4-[cyclohexyl(hydroxyethylcarbamoyl)amino]piperidine-1-yl)-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step B of Intermediate 81 using N-cyclohexyl[(2R)-2-(BOC)amino-3-(4-chlorophenyl)-1-oxo]piperidine-4-yl}carbamoyl chloride.

MS[M+H]=551(M+1)

Intermediate 59-190

The compounds below were prepared following the procedure described in Intermediates 158 using commercially available aminoalcohols or amine compounds prepared in Intermediate 6-35.

Intermediate R R′ R⁴ n * MS (M+ 1 159 H CH₂(CH₂)₃NH(BOC) c-Hex 1 S 664 160 H CH₂(CH₂)₂NH(BOC) c-Hex 1 S 650 161 H CH₂CH₂NH(BOC) c-Hex 1 S 636 162 H CH₂CH₂OH c-Hex 1 S 537 163 CH₂CH₂OH CH₂CH₂OH c-Hex 1 S 581 164 H CH₂CH₂OMe c-Hex 1 S 551 165 3(S)-hydroxy-Pyd-1-yl c-Hex 1 S 563 166 2(S)-hydroxymethyl-Pyd-1-yl c-Hex 1 S 577 167 Me CH₂CH₂OH c-Hex 2 565 168 Et CH₂CH₂OH c-Hex 2 579 169 Pr CH₂CH₂OH c-Hex 2 593 170 c-Pr CH₂CH₂OH c-Hex 2 591 171 CH₂CH₂OMe CH₂CH₂OH c-Hex 2 609 172 Me CH₂CH₂OMe c-Hex 2 579 173 Et CH₂CH₂OMe c-Hex 2 593 174 CH₂CH₂OMe CH₂CH₂OMe c-Hex 2 623 175 Me Et c-Hex 2 563 176 Me OMe c-Hex 2 551 177 Me C(Me)₂CH₂OH c-Hex 2 593 178 Me CH₂CH₂OH 2,3-diF—Ph 2 593 179 Me CH₂CH₂OMe 2,3-diF—Ph 2 609 180 CH₂CH₂F CH₂CH₂OMe c-Hex 2 611 181 3(R)-hydroxy-Pyd-1-yl c-Hex 2 577 182 3(S)-hydroxy-Pyd-1-yl c-Hex 2 577 183 (2R)-hydroxymethyl-Pyd-1-yl c-Hex 2 591 184 (2S)-hydroxymethyl-Pyd-1-yl c-Hex 2 591 185 (3S)-N-BOC-amino-Pyd-1-yl c-Hex 2 576 186 (3R)-N-BOC-amino-Pyd-1-yl c-Hex 2 576 187 (3R)-hydroxy-Pid-1-yl c-Hex 2 591 188 (3S)-hydroxy-Pid-1-yl c-Hex 2 591 189 4-hydroxy-Pid-1-yl c-Hex 2 591 190 4-N-BOC-amino-Pid-1-yl c-Hex 2 590

Intermediate 191: 4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine Step A: 1-BOC-4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine

To a solution of 1-BOC-4-cyclohexylamino)piperidine (282 mg, 1.00 mmol) in DCM (3 mL) was added isopropyl isocyanate (108 μl, 1.10 mmol). After being stirred at rt for 30 min, the reaction solution was concentrated in vacuo, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/5) to give the title compound (354 mg, 94.0%).

MS[M+H]=368(M+1)

Step B: 4-[cyclohexyl(N-isopropylcarbamoyl)amino]piperidine

The title compound was prepared following the procedure described in Step B of Intermediate 1 using 1-BOC-4-[cyclohexyl(N-isopropylcarbamoyl)amino]piperidine.

MS[M+H]=268(M+1)

Intermediate 192: 4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine Step A: 1-BOC-4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine

The title compound was prepared following the procedure described in Step A of Intermediate 128 using 1-BOC-4-[cyclohexyl(isopropylcarbamoyl)amino]piperidine.

MS[M+H]=382(M+1)

Step B: 4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine

The title compound was prepared following the procedure described in Step B of Intermediate 1 using 1-BOC-4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine.

MS[M+H]=282(M+1)

Intermediate 193-198

The compounds below were prepared following the procedure described in Intermediates 128 or Step A of Intermediate 191 using 1-BOC-4-(cyclohexylamino)piperidine and isocyanates or isothiocyanates.

Intermediate X R⁹ R¹⁰ MS (M + 1) 193 O H n-Bu 281 194 O H c-Hex 307 195 O H Ph 301 196 O Me n-Bu 295 197 S H Et 275 198 S Me Et 289

Intermediate 199: methyl[cyclohexyl(piperidin-4-yl)amino]acetate Step A; methyl{cyclohexyl[1-(BOC)piperidin-4-yl]amino}acetate

The title compound was prepared following the procedure described in Step A of Intermediate 128 using 1-BOC-4-(cyclohexylamino)poperidine.

MS[M+H]=355(M+1)

Step B: methyl[cyclohexyl(piperidin-4-yl)amino]acetate

The title compound was prepared following the procedure described in Step B of Intermediate 1 using methyl{cyclohexyl[1-(BOC)piperidin-4-yl]amino}acetate prepared in Step A.

MS[M+H]=255(M+1)

Intermediate 200: (2R)-2-(BOC)amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Intermediate 129 using (2R)-1-BOC-(4-chlorophenyl)alanine and 3-hydroxyazetidine (Syn. Lett., 1991, 783.).

MS[M+H]=355(M+1)

Intermediate 201: (2R)-2-(BOC)amino-N-(3-oxo-azetidine-1-yl)-3-(4-chlorophenyl)propionamide

(2R)-2-(BOC)Amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide (3.54 g, 10 mmol) was placed in a round-bottomed flask, filled with nitrogen, and DCM (30 mL) and oxalyl chloride (872 μl, 10 mmol) were added. The mixture was cooled to −78-C, and DMSO (709 μl, 10 mmol) was added. The reaction solution was stirred for 3 h keeping the temperature below −50° C. The reaction mixture was quenched by addition of TEA and warmed to rt. The reaction solution was diluted with a saturated aqueous NH₄Cl solution, and the organic material was extracted with EtOAc. The extracts was dried over MgSO₄ and concentrated in vacuo, and the residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (2.88 g, 84%).

MS[M+H]=353(M+1)

Intermediate 202: (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Intermediate 2 using (2R)-2-(BOC-amino)-N-(3-oxo-azetidine-1-yl)-3-(4-chlorophenyl)propionamide prepared in Intermediate 201 and cyclohexylamines.

MS[M+H]=437(M+1)

Intermediate 203: (2R)-2-(BOC)amino-N-{3-[cyclohexyl(isobutyryl)amino]azetidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Intermediate 36 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and isobutyrylchloride.

MS[M+H]=507(M+1)

Intermediate 204-217

The compounds below were prepared following the procedure described in Intermediates 201 and 203 using (2R)-2-(BOC)amino-N-(3-hydroxyazetidine-1-yl)-3-(4-chlorophenyl)propionamide prepared in Intermediate 200.

Intermediate R³ * R⁴ R⁵ MS (M + 1) 204 4-Cl-Bn R C(O)C(Me)₃ c-Hex 520 205 4-Cl-Bn R C(O)OMe c-Hex 494 206 4-Cl-Bn R S(O)₂Me c-Hex 515 207 4-Cl-Bn R C(O)N(Me)₂ c-Hex 507 208 4-Cl-Bn R C(O)CH(Me)₂ c-Pen 492 209 4-Cl-Bn R C(O)CH(Me)₂ c-Hep 520 210 4-Cl-Bn R C(O)CH(Me)₂ i-Pr 466 211 4-Cl-Bn R C(O)CH(Me)₂ i-Bu 480 212 4-Cl-Bn R C(O)CH(Me)₂ (c-Hex)-CH₂— 520 213 4-Cl-Bn R C(O)CH(Me)₂ 2-Me-c-Hex 520 214 Bn R C(O)CH(Me)₂ c-Hex 472 215 Bn R C(O)CH(Me)₂ c-Hex 486 216 Bn R C(O)C(Me)₃ c-Hex 500 217 (c-Hex)-CH₂— R C(O)CH(Me)₂ c-Hex 478

Intermediate 218: (2R)-2-(BOC)amino-N-{3-[cyclohexyl(methoxycarbonyl)amino]azetidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Intermediate 135 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and methyl bromoacetate.

MS[M+H]=508(M+1)

The present invention is illustrated by the following examples. However, the scopes of the invention are not limited to these examples.

EXAMPLES Example 1 (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide.TFA Step A: (2R)-2-(BOC-amino)-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine (HCl salt, 917 mg, 3.30 mmol) in DMF (30 mL) were added DIPEA (1.15 mL, 6.70 mmol), (2R)-N-BOC-(4-chlorophenyl)alanine (1.00 mg, 3.30 mmol), HOBT (668 mg, 5.00 mmol), and EDC (845 mg, 4.30 mmol). After being stirred at rt for 12 h, the reaction solution was concentrated in vacuo, and the residue was diluted with a saturated NaHCO₃ solution and EtOAc. The organic layer was extracted with EtOAc and subsequently washed with a saturated aqueous NaHCO₃ solution, water and an aqueous 1N HCl solution. The organic solution was dried over MgSO₄ and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/2) to give the title compound (1.58 g, 93.9%).

MS[M+H]=520(M+1)

Step B: (2R)-2-amino-N-{(3R)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide.TFA

(2R)-2-(BOC-amino)-N-{(3R)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, (1.00 g, 1.93 mmol) was dissolved in DCM (7 mL), and TFA (7 mL) was added dropwise. After the solution was stirred at rt for 1 h, the solvent was removed in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 979 mg, 95.1%).

MS [M+H]=420 (M+1)

Example 2 (2R)-2-{[(2R)-pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide.2TFA Step A: (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Example 1, (100 mg, 0.188 mmol) in DMF (3 mL) were added DIPEA (66.1 mL, 0.381 mmol), EDC (48.7 mg, 0.252 mmol), HOBT (43.6 mg, 0.322 mmol), and (2R)-N-BOC-proline (40.9 mg, 0.190 mmol). After the reaction mixture was stirred at rt for 12 h, DMF was removed in vacuo, and the residue was diluted with a saturated aqueous NaHCO₃ solution and EtOAc. The organic layer was extracted with EtOAc and subsequently washed with a saturated aqueous NaHCO₃ solution, water and an aqueous 1N HCl solution. The organic solution was dried over MgSO₄ and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=2/1) to give the title compound (107 g, 90.8%).

MS [M+H]=617 (+1)

Step B: (2R)-2-{[(2R)-pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]carbonyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, (50.0 mg, 0.081 mmol) in DCM (2 mL) was added TFA (2 mL). After the reaction solution was stirred at rt for 30 min. the solvent was removed in vacuo, and the residue was purified by HPLC to give the title compound (50.0 mg, 98.2%).

MS[M+H]=517(M+1)

Example 3 (2R)-2-{[(2R)-pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Example 1, (TFA salt, 100 mg, 0.191 mmol) and (2R)-N-BOC-proline carboxyaldehyde (39.6 mg, 0.2 mmol) in DCE (3 mL) was added and NaBH(OAc)₃ (96 mg, 4 mmol) at rt. After being stirred 4 h, the reaction mixture was quenched with a saturated aqueous NaHCO₃ solution, and the organic material was extracted with DCM followed by EtOAc. The extracts were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by column chomatography (eluent: DCM/MeOH=9/1) to give the title compound (107 mg, 90.80%).

MS [M+H]=603 (M+1)

Step B: (2R)-2-{[(2R)-pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide(50 mg, 0.0831 mmol), prepared in Step A, in DCM (2 mL) was added TFA (2 mL). After being stirred at rt for 1 h, the reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (58.8 mg, 97.1%).

MS[M+H]=517(M+1)

Example 4 (2R)-2-{methyl[((2R)-pyrrolidine-2-yl)methyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Example 3 using (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 3 and formaline.

MS[M+H]=531(M+1)

Example 5 (2R)-(dimethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Example 3 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TEA prepared in Example 1 and formaline.

MS[M+H]=449(M+1)

Example 6 (2R)-2-[1-(methyl)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-[1-(BOC)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Example 1 and BOC-3-oxo-azetidine.

MS[M+H]=575(M+1)

Step B: (2R)-2-{Fmoc[1-(BOC)azetidine-3-yl]}amino-N-f{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Intermediate 1 using (2R)-2-[1-(BOC)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared Step A.

MS[M+H]=797(M+1)

Step C: (2R)-2-[Fmoc(azetidine-3-yl)]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{Fmoc[1-(BOC)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B

MS[M+H]=697(M+1)

Step D: (2R)-2-{Fmoc[1-(methyl)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-[Fmoc(azetidine-3-yl)]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared Step C.

MS[M+H]=711(M+1)

Step E: (2R)-2-[1-(methyl)azetidine-3-yl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

(2R)-2-{Fmoc[1-(methyl)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step D (71.1 mg, 1 mmol) was dissolved in 50% of piperidine-DMF (2 mL). After being stirred 30 min., the reaction mixture was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (52 mg, 73.5%).

MS[M+H]=489(M+1)

Example 7-186

The compounds below were prepared following the procedure described in Example 1-6 using pyrrolidine, piperidine, or azetidine derivatives prepared in the above Intermediates.

Exm. R¹ R² R³ *1 R⁴ *2 R⁵ n MS (M + 1) 7 H H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 434 8 H H 4-Cl-Bn R c-Hex S C(O)OMe 1 408 9 H H 4-Cl-Bn R c-Hex S C(O)N(Me)₂ 1 421 10 H H 4-Cl-Bn R c-Hex S SO₂Me 1 428 11 H H 4-Cl-Bn R c-Hex S CH₂C(O)OMe 1 422 12 H H 4-Cl-Bn R c-Hex S SO₂NH₂ 1 429 13 H H 4-Cl-Bn R c-Hex S Gly 2 409 14 H H 4-Cl-Bn R c-Hex S CH₂C(O)N(Me)₂ 2 435 15 H H 4-Cl-Bn R c-Hex S CH₂SO₂Me 1 442 16 H H 4-Cl-Bn R c-Hex R C(O)CH(Me)₂ 1 420 17 H H 4-Cl-Bn R c-Hex R C(O)C(Me)₃ 1 434 18 H H 4-Cl-Bn R c-Pen S C(O)CH(Me)₂ 1 406 19 H H 4-Cl-Bn R c-Hep S C(O)CH(Me)₂ 1 434 20 H H 4-Cl-Bn R i-Pr S C(O)CH(Me)₂ 1 480 21 H H 4-Cl-Bn R (c-Hex)-CH₂ S C(O)CH(Me)₂ 1 434 22 H H 4-Cl-Bn R 4,4-diMe-c-Hex S C(O)CH(Me)₂ 1 448 23 H H 4-Cl-Bn R c-Pen R C(O)CH(Me)₂ 1 406 24 H H 4-Cl-Bn S c-Hex S C(O)CH(Me)₂ 1 420 25 H H Bn R c-Hex S C(O)CH(Me)₂ 1 386 26 H H 4-Br-Bn R c-Hex S C(O)CH(Me)₂ 1 465 27 H H 4-MeO-Bn R c-Hex S C(O)CH(Me)₂ 1 416 28 H H 3,4-diCl-Bn R c-Hex S C(O)CH(Me)₂ 1 454 29 H H 4-F-Bn R c-Hex S C(O)CH(Me)₂ 1 404 30 H H 4-HO-Bn R c-Hex S C(O)CH(Me)₂ 1 402 31 H H (c-Hex)-CH₂ R c-Hex S C(O)CH(Me)₂ 1 392 32 H H (indol-2-yl)-CH₂ R c-Hex S C(O)CH(Me)₂ 2 425 33 H H i-Bu R c-Hex S C(O)CH(Me)₂ 1 352 34 H H NH₂C(O)CH₂ R c-Hex S C(O)CH(Me)₂ 1 353 35 H H 4-Cl-Bn R 2,3-diF—Ph S C(O)CH(Me)₂ 1 450 36 H H 4-Cl-Bn R 2,4-diF—Ph S C(O)CH(Me)₂ 1 450 37 H H 4-Cl-Bn R 2,3-diF—Ph R C(O)CH(Me)₂ 1 450 38 H H 4-Cl-Bn R 2,4-diF—Ph R C(O)CH(Me)₂ 1 450 39 Me Me 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 465 40 Ac H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 462 41 MeSO₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 498 42 (Me)₂NC(O)—CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 505 43 Gly H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 477 44 H₂NC(O)—CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 477 45 N-diMe-Gly H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 505 46 N-Ac-Gly H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 519 47 N-Ms-Gly H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 555 48 (R)Ala H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 491 49 β-Ala H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 491 50 β-Ala H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 505 51 N-diMe-β-Ala H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 533 52 4-amino-Bu H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 505 53 (S)Ala H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 491 54 (S)His H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 606 55 N—Me-(S)His H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 620 56 N—Ac-(S)His H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 648 57 N—Ac-(S)His H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 662 58 N—Ms-(S)His H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 684 59 (R)His H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 606 60 (S)Phe H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 567 61 (R)Phe H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 567 62 (R)Pro H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 531 63 N—Me-(R)Pro H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 545 64 (S)Pro H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 517 65 (R)Pid-2-CO H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 531 66 (R)Pid-2-CO H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 1 545 67 1-Me-(R)Pid-2-CO H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 545 68 1-Ac-(R)Pid-2-CO H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 573 69 (S)Pid-2-CO H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 531 70 (R)Tic H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 579 71 (R)Tic H Bn R c-Hex S C(O)CH(Me)₂ 1 545 72 (S)Tic H 4-Cl-Bn R c-Hex R C(O)CH(Me)₂ 1 579 73 cis-Dic H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 583 74

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 503 75

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 545 76

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 570 77

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 574 78

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 546 79

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 560 80

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 504 81

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 532 82 HO—CH₂—C(O) H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 0 478 83

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 489 84 (R)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)C(Me)₃ 2 517 85 (R)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex R C(O)CH(Me)₂ 2 503 86 (R)Pyd-2-CH₂ H 4-Cl-Bn R 2,3-diF—Ph R C(O)CH(Me)₂ 2 533 87 (R)Pyd-2-CH₂ H 4-Cl-Bn R 2,4-DiF—Ph R C(O)CH(Me)₂ 2 533 88 (R)Pyd-2-CH₂ H 4-Cl-Bn R c-Pen S C(O)CH(Me)₂ 2 589 89 (R)Pyd-2-CH₂ H Bn R c-Hex S C(O)CH(Me)₂ 2 569 90 (R)Pyd-2-CH₂ H (c-Hex)-CH₂— R c-Hex S C(O)CH(Me)₂ 2 475 91 (R)-1-Ac-Pyd-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 1 545 92 (S)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 503 93 (S)Pyd-2-CH₂ Me 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 517 94 (S)-1-Me-Pyd-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 517 95 (R)Pid-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 517 96 (R)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 531 97 (R)-1-Me-Pid-2-CH₂ Me 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 559 98 (S)Pid-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 517 99 (S)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 531 100

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 475 101

H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 475 102 1-Me-Pid-4-yl H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 503 103 Pid-4-yl H 4-Cl-Bn R c-Hex S C(O)CH(Me)₂ 2 503 104 Pid-4-yl Me 4-Cl-Bn R c-Hex S C(O)C(Me)₂ 2 517

MS Exm. R¹ R² R³ * R⁴ R⁵ n (M + 1) 105 H H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 434 106 H H 4-Cl-Bn R c-Hex C(O)C(Me)₃ 1 448 107 H H 4-Cl-Bn R c-Hex C(O)OMe 1 422 108 H H 4-Cl-Bn R c-Hex C(O)N(Me)₂ 1 435 109 H H 4-Cl-Bn R c-Hex CH₂C(O)OMe 2 436 110 H H 4-Cl-Bn R c-Hex Gly 1 423 111 H H 4-Cl-Bn R c-Hex CH₂C(O)N(Me)₂ 2 449 112 H H 4-Cl-Bn R c-Hex C(O)NH(i-Pr) 1 449 113 H H 4-Cl-Bn R c-Hex C(O)N(i-Pr)(Me) 1 463 114 H H 4-Cl-Bn R c-Hex C(O)N(Bu) 1 463 115 H H 4-Cl-Bn R c-Hex C(O)N(Bu)(Me) 1 477 116 H H 4-Cl-Bn R c-Hex C(O)N(c-Hex) 1 489 117 H H 4-Cl-Bn R c-Hex C(O)N(Ph) 1 485 118 H H 4-Cl-Bn R c-Hex C(S)N(Et) 1 451 119 H H 4-Cl-Bn R c-Hex C(S)N(Et)(Me) 1 465 120 H H 4-Cl-Bn R c-Hex S(O)₂Me 1 456 121 H H 4-Cl-Bn R c-Pen C(O)CH(Me)₂ 1 420 122 H H 4-Cl-Bn R c-Hep C(O)CH(Me)₂ 1 448 123 H H 4-Cl-Bn R ph C(O)CH(Me)₂ 1 428 124 H H 4-Cl-Bn R 2-MeO—Ph C(O)CH(Me)₂ 1 458 125 H H 4-Cl-Bn R 3-MeO—Ph C(O)CH(Me)₂ 1 458 126 H H 4-Cl-Bn R 2-Cl—Ph C(O)CH(Me)₂ 1 462 127 H H 4-Cl-Bn R 2-F—Ph C(O)CH(Me)₂ 1 446 128 H H 4-Cl-Bn R 3-F—Ph C(O)CH(Me)₂ 1 446 129 H H 4-Cl-Bn R 4-F—Ph C(O)CH(Me)₂ 1 446 130 H H 4-Cl-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 1 464 131 H H 4-Cl-Bn R 2,4-diF—Ph C(O)CH(Me)₂ 1 464 132 H H 4-Cl-Bn R 2,5-diF—Ph C(O)CH(Me)₂ 1 464 133 H H 4-Cl-Bn R 2,6-diF—Ph C(O)CH(Me)₂ 1 464 134 H H 4-Cl-Bn R 3,4-diF—Ph C(O)CH(Me)₂ 1 464 135 H H 4-Cl-Bn R 2-F-4-MeO—Ph C(O)CH(Me)₂ 1 476 136 H H 4-Cl-Bn S c-Hex C(O)CH(Me)₂ 1 434 137 H H 4-Br-Bn R c-Hex C(O)CH(Me)₂ 1 479 138 H H 3,4-di-F-Bn R c-Hex C(O)CH(Me)₂ 1 468 139 H H 4-F-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 1 448 140 H H 4-HO-Bn R c-Hex C(O)CH(Me)₂ 1 416 141 H H 4-MeO-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 1 448 142 H H (c-Hex)-CH₂ R c-Hex C(O)CH(Me)₂ 1 406 143 N-diMe-Gly H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 519 144 (R)Ala H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 505 145 β-Ala H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 519 146 N-diMe-β-Ala H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 547 147 (S)His H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 620 148 (R)Pro H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 531 149 N—Me-(R)Pro H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 617 150 (R)Tic H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 591 151 (R)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 517 152 (R)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex C(O)C(Me)₃ 2 531 153 (R)Pyd-2-CH₂ H 4-Cl-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 2 547 154 (R)Pyd-2-CH₂ H 4-Cl-Bn R 2,4-diF—Ph C(O)CH(Me)₂ 2 547 155 (S)Pyd-2-CH₂ H 4-F-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 2 547 156 (2R, 4S)-4F-Pyd-2-CH₂ H 4-Cl-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 2 554 157 (S)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 517 158 (S)Pyd-2-CH₂ H 4-Cl-Bn R 2,3-diF—Ph C(O)CH(Me)₂ 2 547 159 (S)Pyd-2-CH₂ H 4-Cl-Bn R 2,4-diF—Ph C(O)CH(Me)₂ 2 547 160 (R)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 545 161 (R)-1-Me-Pid-3-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 545

Example R¹ R² R³ * R⁴ R⁵ n MS (M + 1) 162 H H 4-Cl-Bn c-Hex C(O)CH(Me)₂ 1 406 163 H H 4-Cl-Bn R c-Hex C(O)C(Me)₃ 1 420 164 H H 4-Cl-Bn R c-Hex C(O)OMe 1 394 165 H H 4-Cl-Bn R c-Hex C(O)N(Me)₂ 1 407 166 H H 4-Cl-Bn R c-Hex S(O)₂Me 1 414 167 H H 4-Cl-Bn R c-Pen C(O)CH(Me)₂ 1 392 168 H H 4-Cl-Bn R c-Hep C(O)CH(Me)₂ 1 420 169 H H 4-Cl-Bn R i-Pr C(O)CH(Me)₂ 1 466 170 H H 4-Cl-Bn R (c-Hex)-CH₂ C(O)CH(Me)₂ 1 420 171 H H 4-Cl-Bn R 2-Me-(c-Hex) C(O)CH(Me)₂ 1 420 172 H H 4-Cl-Bn R i-Bu C(O)CH(Me)₂ 1 480 173 Gly H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 463 174 N-diMe-Gly H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 505 175 (S)His H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 592 176 N—BOC-(S)His H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 692 177 (R)Pro H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 503 178 N—Me-(R)Pro H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 517 179 (S)Pro H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 503 180 (R)Pid-2-CO H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 517 181 N—Me-(R)Pid-2-CO H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 531 182 (R)Tic H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 1 565 183

H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 489 184 (R)Pyd-2-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 589 185 (R)-1-Me-Pid-2-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 631 186 (R)Pid-2-CH₂ H 4-Cl-Bn R c-Hex C(O)CH(Me)₂ 2 617

Example 187 (2R)-2-amino-N-{(3S)-3-{[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl Step A: (2R)-2-(BOC)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 1 using 3(S)-3-{cyclohexyl[(2R)-2-methyl-3-acetyloxypropionyl]amino}pyrrolidine.

MS[M+H]=520(M+1)

Step B: (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

To a solution of (2R)-2-(BOC)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, in DCM (7 mL) was added TFA (7 mL). After being stirred at rt for 1 h, the reaction mixture was concentrated iii vacuo to give the title compound. The product was used without further purification.

MS[M+1]=420(M+1)

Step C: (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-propionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Step B, (592 mg, 1.00 mmol) in MeOH/H₂O=1/1, 10 mL) was added LiOH (70 mg, 2.00 mmol) portionwise. After the reaction mixture was stirred at rt for 30 min., the solvent was removed in vacuo, and the residue was dilute with a saturatd aqueous NaHCO₃ solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO₄ and concentrated in vacu. The residue was purified by HPLC to give the title compound (495 mg, 90.0%).

MS[M+1]=420(M+1)

Step D: (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

(2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in the above Step C was dissolved in methanol, and passed though HCl-substituted ion exchange resin to give the title compound.

MS[M+1]=420(M+1)

Example 188 (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl Step A: (2R)-2-[(BOC)aminoacetyl]amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 1 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 187 and N-BOC-Gly.

MS[M+H]=635(M+1)

Step B: (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step B of Example 187 using (2R)-2-[(BOC)aminoacetyl]amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A.

MS[M+H]=535(M+1)

Step C: (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B.

MS[M+H]=493(M+1)

Step D: (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-(aminoacetyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step C.

MS[M+H]=493(M+1)

Example 189 (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl Step A: (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Step B of Example 187, (592 mg, 1.00 mmol) and formaline (0.72 mL, 10.0 mmol) in DCE (3 mL) was added NaBH(OAc)₃ (460 mg, 2.00 mmol). After the being stirred at rt for 4 h, the reaction mixture was quenched with an aqueous NaHCO₃ solution and extracted with DCM followed by EtOAc. The extracts were dried over MgSO₄ and concentrated in vacuo, and the residue was purified by column chomatography (eluent: DCM/MeOH=9/1) to give the title compound (512 mg, 90.0%).

MS[M+H]=563(M+1)

Step B: (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A.

MS[M+H]=521(M+1)

Step C: (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-(dimethyl)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-hydroxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in the above Step B.

MS[M+H]=521(M+1)

Example 190-293

The compounds below were prepared following the procedure described in Example 187-189 using pyrrolidine and piperidine derivatives prepared in the above Intermediates.

MS Exm. R¹ R² Y R⁴ R^(5′) * n x [M + 1] 190 H H Cl c-Hex C(Me)₂CH₂OH S 1 1 464 191 H H Cl c-Hex C(Me)₂OH S 1 1 436 192 H H Cl c-Hex C(Me)₂(CH₂)₂OH S 1 1 478 193 H H Cl c-Hex C(Me)(CH₂OH)₂ S 1 1 466 194 H H Cl c-Hex C(Me)₂CH₂OH R 1 1 464 195 H H Cl c-Hex C(Me)₂CH₂OMe S 1 1 464 196 H H Cl c-Hex C(Me)₂CH₂OBn S 1 1 540 197 H H Cl c-Hex C(—(CH₂)₄—)CH₂OH S 1 1 464 198 H H Cl c-Hex C(Me)₂(CH₂)₃O-(2,4-diMe—Ph) S 1 1 582 199 H H Cl c-Hex C(Me)CH₂OAc S 1 1 478 200 H H Cl c-Hex C(—(CH₂)₂—)C(O)OH S 1 1 461 201 H H Cl c-Hex N(n-Pr) S 1 2 450 202 H H Cl c-Hex N(Et) S 1 2 436 203 H H Cl c-Hex N(n-Bu) S 1 2 464 204 H H Cl c-Hex 3-OH—Ph S 1 1 470 205 H H Cl c-Hex 4-OH—Ph S 1 1 470 206 H H Cl c-Hex 2-(CH₂OH)-1-(c-penten)-1-yl S 1 1 474 207 H H Cl c-Hex 2-(CH₂OH)-1-(c-Hexen)-1-yl S 1 1 488 208 H H Cl c-Hex 1-Nos-Pid-4-yl S 1 1 646 209 H H Cl c-Hex Pid-4-yl S 1 2 461 210 H H Cl c-Hex C(OH)(i-Pr) S 1 1 449 211 H H Cl c-Hex CH₂C(Me)₂OH S 1 1 449 212 H H Cl c-Hex

S 1 1 475 213 H H Cl c-Hex

S 1 1 447 214 H H H c-Hex C(Me)₂CH₂OH S 1 1 415 215 H H F c-Hex C(Me)₂CH₂OH S 1 1 433 216 H H Me c-Hex C(Me)₂CH₂OH S 1 1 429 217 H H MeO c-Hex C(Me)₂CH₂OH S 1 1 445 218 Me Me Cl c-Hex C(Me)₂CH₂OH S 1 1 478 219 Me Me Cl c-Hex C(Me)(CH₂OH)₂ S 1 1 494 220 Me Me Cl c-Hex

S 1 1 520 221 Me Me H c-Hex C(Me)₂CH₂OH S 1 1 443 222 Me Me F c-Hex C(Me)₂CH₂OH S 1 1 461 223 Me Me Me c-Hex C(Me)₂CH₂OH S 1 1 457 224 Me Me MeO c-Hex C(Me)₂CH₂OH S 1 1 473 225 Et Et Cl c-Hex C(Me)₂CH₂OH S 1 1 506 226 iPr H Cl c-Hex C(Me)₂CH₂OH S 1 1 492 227 —(CH₂)₅— Cl c-Hex C(Me)₂CH₂OH S 1 1 518 228 HOCH₂C(Me)₂C(O) H Cl c-Hex C(Me)₂CH₂OH S 1 0 550 229 Imidazol-2-yl H Cl c-Hex C(Me)₂CH₂OH S 1 2 530 230 Imidazol-4-yl H Cl c-Hex C(Me)₂CH₂OH S 1 2 530 231 (i-Pr)C(O) H Cl c-Hex C(Me)₂CH₂OH S 1 0 520 232 Gly H Cl c-Hex C(Me)CH₂OH S 1 1 507 233 NH₂—(CH₂)₄ H Cl c-Hex C(Me)₂CH₂OH S 1 1 535 234 N-diMe-Gly H Cl c-Hex C(Me)₂CH₂OH S 1 1 535 235 HO—(CH₂)₃—C(O) H Cl c-Hex C(Me)₂CH₂OH S 1 0 536 236 EtC(O) H Cl c-Hex C(Me)₂CH₂OH S 1 0 506 237 Pyd-3-yl H Cl c-Hex C(Me)₂CH₂OH S 1 2 519 238 (S)Pyd-2-CH₂— H Cl c-Hex C(Me)₂CH₂OH S 1 2 533 239 MeOC(O)CH₂ H Cl c-Hex C(Me)₂CH₂OH S 1 0 522 240 DTic H Cl c-Hex C(Me)₂CH₂OH S 1 1 609 241 NH₂—(CH₂)₂ H Cl c-Hex C(Me)₂CH₂OH S 1 2 493 242 (Me)NH—(CH₂)₂ H Cl c-Hex C(Me)₂CH₂OH S 1 2 507 243 Pyd-2-CH₂— H Cl c-Hex 2-(CH₂OH)-1-(c-Penen)-1-yl S 1 2 557 244 H H Cl 4-cis-Me-c-Hex C(Me)₂CH₂OH S 1 1 464 245 H H Cl 4-trans-Me-c-Hex C(Me)₂CH₂OH S 1 1 464 246 H H Cl 4-t-Bu-c-Hex C(Me)₂CH₂OH S 1 1 506 247 H H Cl 4-Ph-c-Hex C(Me)₂CH₂OH S 1 1 526 248 H H Cl 4,4-diMe-c-Hex C(Me)₂CH₂OH S 1 1 478 249 H H Cl Pid-4-yl C(Me)₂CH₂OH S 1 2 451 250 H H Cl 4-oxo-c-Hex C(Me)₂CH₂OH S 1 1 464 251 H H Cl 4,4-diF-c-Hex C(Me)₂CH₂OH S 1 1 486 252 H H Cl 4-OH-c-Hex C(Me)₂CH₂OH S 1 1 466 253 H H Cl 4-F-c-Hex C(Me)₂CH₂OH S 1 1 468 254 H H Cl Spiro[2,5]octane C(Me)₂CH₂OH S 1 1 476 255 H H Cl 4-cis-Et-c-Hex C(Me)₂CH₂OH S 1 1 478 256 H H Cl 4-trans-Et-c-Hex C(Me)₂CH₂OH S 1 1 478 257 H H Cl 4-cis-Me-c-Hex C(Me)(CH₂OH)₂ S 1 1 480 258 H H Cl 4-trans-Me-c-Hex C(Me)(CH₂OH)₂ S 1 1 480 259 H H Cl 4,4-diMe-c-Hex C(Me)(CH₂OH)₂ S 1 1 494 270 Me Me Cl 4-cis-Me-c-Hex C(Me)₂CH₂OH S 1 1 492 271 Me Me Cl 4-trans-Me-c-Hex C(Me)₂CH₂OH S 1 1 492 272 Me Me Cl 4-t-Bu-c-Hex C(Me)₂CH₂OH S 1 1 534 273 Me Me Cl 4,4-diMe-c-Hex C(Me)₂CH₂OH S 1 1 514 274 Me Me Cl 4-cis-Et-c-Hex C(Me)₂CH₂OH S 1 1 506 275 Me Me Cl 4-trans-Et-c-Hex C(Me)₂CH₂OH S 1 1 506 276 Me Me Cl 4-cis-Me-c-Hex C(Me)(CH₂OH)₂ S 1 1 508 277 Me Me Cl 4-trans-Me-c-Hex C(Me)(CH₂OH)₂ S 1 1 508 278 Me Me Cl 4,4-diMe-c-Hex C(Me)(CH₂OH)₂ S 1 1 522 279 H H Cl 2,3-diF—Ph C(Me)₂CH₂OH S 1 1 480 280 H H Cl 3,5-DiMe—Ph C(Me)₂CH₂OH R,S 1 1 472 281 H H Cl 2,5-diF—Ph C(Me)₂CH₂OH R,S 1 1 480 282 H H Cl 4-Me—Ph C(Me)₂CH₂OH R,S 1 1 458 283 H H Cl Ph C(Me)₂CH₂OH R,S 1 1 444 284 H H Cl 2-Adamantyl C(Me)₂CH₂OH S 1 1 472 285 H H Cl c-Hex C(Me)₂CH₂OH R 2 1 464 286 H H Cl c-Hex C(Me)(CH₂OH)₂ R 2 1 479 287 H H Cl c-Hex 2-(CH₂OH)-1-(c-penten)-1-yl S 2 1 488 288 H H Cl c-Hex 2-(CH₂OH)-1-(c-hexen)-1-yl S 2 1 502 289 H H Cl 4-cis-Me-c-Hex C(Me)₂CH₂OH S 2 2 477 290 H H Cl 4,4-diMe-c-Hex C(Me)₂CH₂OH S 2 2 591 291 H H Cl 4-trans-Me-c-Hex C(Me)₂CH₂OH S 2 2 493 292 (R)Pyd-2-CH₂— H Cl 2,3-diF—Ph C(Me)₂CH₂OH S 2 2 576 293 (R)Pyd-2-CH₂— H Cl c-Hex C(Me)₂CH₂OH S 2 2 546

Example 294 (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl Step A: (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step A of Example 189 using (2R)-2-(isopropyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrroridine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Example 226 (purified by HPLC).

MS[M+H]=492(M+1)

Step B: (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[isopropyl(methyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine 1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step A.

MS[M+H]=492(M+1)

Example 295 (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl Step A: (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Example 190, (492 mg, 1.00 mmol) in acetonitrile (5 mL) were added DIEA (0.435 mL, 2.50 mmol) was added dropwise and methylbromoacetate (0.085 mL, 1.00 mmol). After the reaction mixture was stirred at 60° C. for 4 h, the solvent was removed in vacuo, and the residue was diluted with an aqueous NaHCO₃ solution. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO₄, and concentrated in vacuo to give the title compound. The product was used without further purification.

MS[M+H]=564(M+1)

Step B: (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step A.

MS[M+H]=508(M+1)

Step C: (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[(2-hydroxy-2-oxo)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step B.

MS[M+H]=508(M+1)

Example 296 (2R)-2-[di(hydroxyacetyl)]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

The title compound was prepared following the procedure described in Example 295 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide. MS[M+H]=566(M+1)

Example 297 (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl Step A: (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step B of Example 187 using (3S)-3-[cyclohexyl[4-(BOC)aminobutylcarbamoyl]amino]pyrrolidine prepared in Intermediate 159.

MS[M+H]=549(M+1)

Step B: (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(4-aminobutylcarbamoyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step A.

MS[M+H]=549(M+1)

Example 298-357

The compounds below were prepared following the procedure described in Example 189 and 297 using pyrrolidine and piperidine derivatives prepared in the above Intermediates.

MS Exm. R¹ R⁴ R^(5′) * n x [M + 1] 298 H c-Hex N—(CH₂)₃—NH₂ S 1 2 450 299 H c-Hex N—(CH₂)₂—NH₂ S 1 2 436 300 H c-Hex N—(CH₂)₂—OH S 1 1 437 301 H c-Hex N—(CH₂)₂—OMe S 1 1 451 302 H c-Hex (3S)-3-(OH)-Pyd-1-yl S 1 1 463 303 H c-Hex (2S)-2-(HOCH₂)-Pyd-1-yl S 1 1 477 304 H c-Hex N[(CH₂)₂OH]₂ S 1 1 495 305 H c-Hex N[(CH₂)₃OH]₂ S 1 1 523 306 H c-Hex N(Me)(CH₂)₂OH 2 1 465 307 H c-Hex N(Et)(CH₂)₂OH 2 1 479 308 H c-Hex N(Et)(CH₂)₃OH 2 1 493 309 H c-Hex N(Et)(CH₂)₂F 2 1 481 310 H c-Hex N(Et)(CH₂)₃F 2 1 495 311 H c-Hex N(n-Pr)(CH₂)₂OH 2 1 493 312 H c-Hex N(c-Pr)(CH₂)₂OH 2 1 491 313 H c-Hex N(i-Pr)(CH₂)₂OH 2 1 493 314 H c-Hex N[(CH₂)₂OMe](CH₂)₂OH 2 1 509 315 H c-Hex N[(CH₂)₂F](CH₂)₂OH 2 1 497 316 H c-Hex N(Me)(CH₂)₂OMe 2 1 479 317 H c-Hex N(H)(CH₂)₂OMe 2 1 465 318 H c-Hex N(Et)(CH₂)₂OMe 2 1 493 319 H c-Hex N[(CH₂)₂OMe]₂ 2 1 523 320 H c-Hex N(c-Pen)[(CH₂)₂OMe] 2 1 533 321 H c-Hex N(Et)₂ 2 1 463 322 H c-Hex N(Me)OMe 2 1 451 323 H c-Hex N(Me)[C(O)(Me)₂CH₂OH] 2 1 493 324 H c-Hex N[(CH₂)₂OMe][(CH₂)₂F] 2 1 511 325 H c-Hex (3S)-3-(OH)-Pyd-1-yl 2 1 477 326 H c-Hex (3R)-3-(OH)-Pyd-1-yl 2 1 477 327 H c-Hex (2R)-2-(HOCH₂)-Pyd-1-yl 2 1 491 328 H c-Hex (2S)-2-(HOCH₂)-Pyd-1-yl 2 1 491 329 H c-Hex (3R)-3-amino-Pyd-1-yl 2 1 476 330 H c-Hex (3S)-3-amino-Pyd-1-yl 2 1 476 331 H c-Hex (3R)-3-(OH)-Pid-1-yl 2 1 491 332 H c-Hex (3S)-3-(OH)-Pid-1-yl 2 1 491 333 H c-Hex 4-(OH)-Pid-1-yl 2 1 491 334 H c-Hex 4-amino-Pid-1-yl 2 1 490 335 (R)Pyd-2-CH₂ c-Hex N(n-Pr)(CH₂)₂OH 2 2 576 336 (R)Pyd-2-CH₂ c-Hex N[(CH₂)₂OH]₂ 2 2 578 337 (R)Pyd-2-CH₂ c-Hex N(Me)OMe 2 2 534 338 (R)Pyd-2-CH₂ c-Hex N(Me)[C(Me)₂CH₂OH] 2 2 562 339 (R)Pyd-2-CH₂ c-Hex N(Et)(CH₂)₂OH 2 2 576 340 (R)Pyd-2-CH₂ c-Hex N[(CH₂)₂OMe]₂ 2 2 620 341 (R)Pyd-2-CH₂ c-Hex N(c-Pr)(CH₂)₂OH 2 2 588 342 (R)Pyd-2-CH₂ c-Hex (3S)-3-(OH)-Pyd-1-yl 2 2 560 343 (R)Pyd-2-CH₂ c-Hex (2R)-2-(HOCH₂)-Pyd-1-yl 2 2 574 344 (R)Pyd-2-CH₂ c-Hex 4-(OH)-Pid-1-yl 2 2 574 345 (R)Pyd-2-CH₂ c-Hex (3R)-3-(OH)-Pid-1-yl 2 2 574 346 (S)Pyd-3-yl c-Hex N[Et]₂ 2 2 532 347 (S)Pyd-3-yl c-Hex N(Me)(CH₂)₂OH 2 2 548 348 NH₂—(CH₂)₂— c-Hex N[(CH₂)₂OH]₂ 2 2 552 349 (Me)NH—(CH₂)₂ c-Hex N[(CH₂)₂OH]₂ 2 2 566 350 (i-Pr)NH—(CH₂)₂— c-Hex N(Et)(CH₂)₂OH 2 2 564 351 Mor-(CH₂)₂ c-Hex N(c-Pr)(CH₂)₂OH 2 2 604 352 Mor-(CH₂)₂ c-Hex N(Et)(CH₂)₂OH 2 2 592 353 Mor-(CH₂)₂ c-Hex N[(CH₂)₂OMe]₂ 2 2 636 354 H 2,3-diF—Ph N(Me)(CH₂)₂OH 2 1 495 355 H 2,3-diF—Ph N(Me)(CH₂)₂OMe 2 1 495 356 (R)Pyd-2-CH₂ 2,3-diF—Ph N(Me)(CH₂)₂OH 2 2 578 357 (R)Pyd-2-CH₂ 2,3-diF—Ph N(Me)(CH₂)₂OMe 2 2 592

Example 358 (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA, prepared in Example 1 (420 mg, 1 mmol), in DM F (10 mL) were added TEA (280 μl, 2 mmol) and (2-nitrobenzene)sulfonylchloride (222 mg, 1.00 mmol). After the being stirred at rt for 4 h, the reaction mixture was quenched with a saturated aqueous NH₄Cl solution and was extracted with DCM followed by EtOAc. The extracts were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/3) to give the title compound (568 mg, 94.0%).

MS[M+H]=585(M+1)

Step B: (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide(200 mg. 0.331 mmol), prepared in Step A, in DMF (3 mL) were added K₂CO₃ and 2-(dimethylamino)ethyl chloride (HCl salts, 73.9 mg, 0.533 mmol). After being stirred at rt for 24 h, the reaction mixture was concentrated in vacuo, and the residue was diluted a saturated aqueous NH₄Cl solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (205 mg, 92.0%).

MS[M+H]=585(M+1)

Step C: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

To a solution of (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide (100 mg, 0.148 mmol), prepared in Step B, in DMF (3 mL) were added K₂CO₃ (61.3 mg, 0.429 mmol) and thiobenzene (45.6 μl, 0.429 mmol). After being stirred at rt for 2 h, the reaction mixture was concentrated in vacuo to remove DMF, and the residue was diluted with water. The organic material was extracted with EtOAc, and the extracts were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by HPLC to give the title compound (89 mg, 84.0%).

MS[M+H]=470(M+1)

Example 359 (2R)-2-[2-(methylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-{(2-nitrobenzene)sulfonyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step B of Example 358 using (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 358 and N-BOC-aminoethylbromide.

MS[M+H]=642(M+1)

Step B: ((2R)-2-{(2-nitroenzene)sulfonyl[2-(methyl(BOC)amino)ethyl]}amino-N-{(3S)-3-[(cyclohexyl(isobutyryl)amino)pyrrolidine-1-yl]-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 128 using (2R)-2-{(2-nitrobenzene)sulfonyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A and methyliodide.

MS[M+H]=657(M+1)

Step C: (2R)-2-{2-[methyl(BOC)amino]ethyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step C of Example 358 using (2R)-2-{[2-BOC(methyl)amino]ethyl(2-nitrobenzenesulfonyl)}amino-N-{(3S)-3-[(cyclohexyl(isobutyryl)amino)pyrrolidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Step B.

MS[M+H]=657(M+1)

Step D: (2R)-2-[2-(methylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{2-[methyl(BOC)amino]ethyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step C.

MS[M+H]=657(M+1)

Example 360 (2R)-2-(2-aminoethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step C of Example 358 using (2R)-2-{(2-nitrobenzene)sulfonyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 359.

MS[M+H]=563(M+1)

Step B: (2R)-2-(2-aminoethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A.

MS[M+H]=463(M+1)

Example 361 (2R)-2-[2-(acetylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Example 358 using acetylaminoethyl bromide.

MS[M+H]=505(M+1)

Example 362 (2R)-2-{methyl[2-(methylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 360 and formaline.

MS[M+H]=577(M+1)

Step B: (2R)-2-{methyl[2-(methyl(BOC)amino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 128 using (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A and methyliodide.

MS[M+H]=591(M+1)

Step C: (2R)-2-{methyl[2-(methylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{methyl[2-[methyl(BOC)amino]ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B.

MS[M+H]=491(M+1)

Example 363 (2R)-2-{methyl[2-(amino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step B of Example 1 using (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 362.

MS[M+H]=477(M+1)

Example 364 (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-{methyl[(2-nitrobenzene)sulfonyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step B of Example 358 using (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(isopropyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 358 and methyliodide.

MS[M+H]=619(M+1)

Step B: (2R)-(methyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step Cof Example 358 using (2R)-2-{methyl[(2-nitrobenzene)sulfonyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A.

MS[M+H]=434(M+1)

Example 365-388

The compounds below were prepared following the procedure described in Example 358 and 364 using piperidine derivatives prepared in the above Intermediates.

MS Example R¹ R² R³ *1 *2 R⁴ n (M + 1) 365 MeO₂C—CH₂ H 4-Cl-Bn R S C(O)CH(Me)₂ 2 492 366 N-Me-Gly H 4-Cl-Bn R S C(O)CH(Me)₂ 1 491 367 N-Me-β-Ala H 4-Cl-Bn R S C(O)CH(Me)₂ 1 505 368 (Me)NH—(CH₂)₂ H 4-Cl-Bn R R C(O)CH(Me)₂ 2 477 369 (Me)₂N—(CH₂)₂ H 4-Cl-Bn R S C(O)C(Me)₃ 2 505 370 (Me)₂N—(CH₂)₂ H Bn R S C(O)CH(Me)₂ 2 457 371 (Me)₂N—(CH₂)₂ H (c-Hex)-CH₂— R S C(O)CH(Me)₂ 2 463 372 (Me)₂N—(CH₂)₂ Me 4-Cl-Bn R S C(O)CH(Me)₂ 2 484 373 (Et)₂N—(CH₂)₂ H 4-Cl-Bn R S C(O)CH(Me)₂ 2 519 374 [Me(Et)]N—(CH₂)₂ H 4-Cl-Bn R S C(O)CH(Me)₂ 2 505 375 (aziridine-1-yl)-(CH₂)₂ H 4-Cl-Bn R S C(O)CH(Me)₂ 2 489 376 (3R)Pyd-3-yl H 4-Cl-Bn R S C(O)CH(Me)₂ 2 489 377 (azetidine-2-yl)-CO H 4-Cl-Bn R S C(O)CH(Me)₂ 2 503 378 Pyd-1-(CH₂)₂ H 4-Cl-Bn R S C(O)CH(Me)₂ 2 517

Example R¹ R² R³ * R⁴ n MS (M + 1) 379 Me H 4-Cl-Bn R C(O)CH(Me)₂ 1 448 380 MeO₂C—CH₂ H 4-Cl-Bn R C(O)CH(Me)₂ 1 506 381 NH₂—(CH₂)₂ H 4-Cl-Bn R C(O)CH(Me)₂ 2 477 382 (Me)₂N—(CH₂)₂ H 4-Cl-Bn R C(O)CH(Me)₂ 2 505 383 (3R)Pyd-3-yl H 4-Cl-Bn R C(O)CH(Me)₂ 2 503 384 (3R)Pyd-3-yl H Bn R C(O)CH(Me)₂ 2 489

Example R¹ R² R³ * R⁴ n MS (M + 1) 385 MeO₂C—CH₂ H 4-Cl-Bn R C(O)CH(Me)₂ 1 478 386 (Me)₂N—(CH₂)₂ H 4-Cl-Bn R C(O)CH(Me)₂ 2 505 387 (Me)₂N—(CH₂)₂ H 4-Cl-Bn R C(O)C(Me)₃ 2 519 388 Pyd-1-(CH₂)₂ H 4-Cl-Bn R C(O)CH(Me)₂ 2 503

Example 389 (2R)-2-[(dimethylamino)methylene]amino-N-{(3S)-3-{[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

(2R)-2-amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA (51.4 mg, 0.1 mmol) and dimethylformamide dimethoxyformat (0.24 mg, 0.2 mmol) were dissolved in methanol (5 mL). After the reaction mixture was stirred at rt for 1 h, the solvent was distilled out in vacuo to remove, the residue was purified by HPLC to give the title compound (46 mg, 99%).

MS[M+H]=477 (M+1)

Example 390 (2R)-2-(carboxymethyl)amino-N-{(3S)-3-{[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step B of Example 135 using Example 365.

MS[M+H]=478 (M+1)

Example 391 (2R)-2-(carboxymethyl)amino-N-{4-[cyclohexyl(isobutyryl)amino]piperidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step B of Example 135 using Example 380.

MS[M+H]=492 (M+1)

Example 392 (2R)-2-(carboxymethyl)amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]azetidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

The title compound was prepared following the procedure described in Step B of Example 135 using Example 385.

MS[M+H]=464 (M+1)

Example 393 (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-yl}-3-(4-chlorophenyl)propionamide 2HCl Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-3-(4-chlorophenyl)propionic acid methylester

The title compound was prepared following the procedure described in Step C of Example 151 using p-chlorophenylalanine methylester.

MS[M+H]=399(M+1)

Step B: (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid methylester

To a solution of (2R)-2-[(2-nitrobenzene)sulfonyl]amino-3-(4-chlorophenyl)propionic acid methylester (1 g, 2.51 mmol), prepared in Step A, in DMF (10 mL) were added K₂CO₃ (678 mg, 5.00 mmol) and methyliodide (427 mg, 3.01 mmol). After the reaction solution was stirred at rt for 12 h, the solvent was concentrated in vacuo, and the residue was diluted with aqueous 1n HCl solution. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO₄, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (932 mg, 90.0%).

MS[M+H]=413(M+1)

Step C: (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid

The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid methyl ester prepared in Step B.

MS[M+H]=399(M+1)

Step D: (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 188 using (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-3-(4-chlorophenyl)propionic acid prepared in Step B and (3S)-3-N-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine prepared in Intermediate 81.

MS[M+H]=521(M+1)

Step E: (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

To a solution of (2R)-2-{[(2-nitrobenzene)sulfonyl]methyl}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step D, (691 mg, 1.00 mmol) in DMF (5 mL) were added K₂CO₃ (270 mg, 2.00 mmol) and mercaptobenzene (0.154 mL, 1.5 mmol), and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was diluted with aqueous 1N HCl solution. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO₄, and concentrated in vacuo to give the title compound. This product was used without further purification.

MS[M+H]=506(M+1)

Step F: (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step C of Example 187 using (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step E.

MS[M+H]=464(M+1)

Step G: (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-(methyl)amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step F.

MS[M+H]=464(M+1)

Example 394 (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step A of Example 358 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Example 190 and 2-nitrobenzenesulfonylchloride.

MS[M+H]=677(M+1)

Step B: (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide

The title compound was prepared following the procedure described in Step B of Example 358 using (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide prepared in Step A and dimethylaminoethylchloride.

MS[M+H]=748(M+1)

Step C: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide

The title compound was prepared following the procedure described in Step C of Example 358 using (2R)-2-{(2-nitrobenzene)sulfonyl[2-(dimethylamino)ethyl]}amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide prepared in Step B.

MS[M+H]=565(M+1)

Step D: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

The title compound was prepared following the procedure described in Step B of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(acetyloxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl) propionamide prepared in Step C.

MS[M+H]=521(M+1)

Step E: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step D.

MS[M+H]=521(M+1)

Example 395-463

The compounds below were prepared following the procedure described in Example 394 using pyrrolidine or piperidine derivatives prepared in the above Intermediates.

MS Exm. R¹ R² X R⁴ R^(5′) * n x [M + 1] 395 Me H Cl c-Hex C(Me)(CH₂OH)₂ S 1 1 480 396 Me H Cl c-Hex C(Me)₂CH₂OMe S 1 1 478 397 Me H Cl c-Hex C(Me)₂CH₂OMOM S 1 1 508 398 Me H Cl c-Hex

S 1 1 462 399 Me H Cl 4-cis-Me-c-Hex C(Me)₂CH₂OH S 1 1 478 400 Me H Cl 4-trans-Me-c-Hex C(Me)₂CH₂OH S 1 1 478 401 Me H Cl 4-diMe-c-Hex C(Me)₂CH₂OH S 1 1 492 402 Me H Cl 4-t-Bu-c-Hex C(Me)₂CH₂OH S 1 1 520 403 Me H Cl 4,4-diF-c-Hex C(Me)₂CH₂OH S 1 1 500 404 Me H Cl Spiro[2.5]octane C(Me)₂CH₂OH S 1 1 490 405 Me H Cl 4-F-c-Hex C(Me)₂CH₂OH S 1 1 482 406 Me H Cl 4-cis-Et-c-Hex C(Me)₂CH₂OH S 1 1 492 407 Me H Cl 4-trans-Et-c-Hex C(Me)₂CH₂OH S 1 1 492 408 Me H Cl 4-cis-Me-c-Hex C(Me)(CH₂OH)₂ S 1 1 494 409 Me H Cl 4-trans-Me-c-Hex C(Me)(CH₂OH)₂ S 1 1 494 410 Me H Cl 4-diMe-c-Hex C(Me)(CH₂OH)₂ S 1 1 508 411 Me H H c-Hex C(Me)₂CH₂OH S 1 1 430 412 Me H F c-Hex C(Me)₂CH₂OH S 1 1 448 413 Me H Me c-Hex C(Me)₂CH₂OH S 1 1 444 414 Me H OMe c-Hex C(Me)₂CH₂OH S 1 1 460 415 i-Pr H Cl 4-cis-Me-c-Hex C(Me)₂CH₂OH S 1 1 506 416 i-Pr H Cl 4,4-diMe-c-Hex C(Me)₂CH₂OH S 1 1 520 417 i-Pr H Cl 4,4-diF-c-Hex C(Me)₂CH₂OH S 1 1 528 418 —(CH₂)₄— Cl c-Hex C(Me)₂CH₂OH S 1 1 520 419 —(CH₂)₅— Cl c-Hex C(Me)₂CH₂OH S 1 1 534 420 i-Pen H Cl c-Hex C(Me)₂CH₂OH S 1 1 520 421 MeO—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OH S 1 1 508 422 HO—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OH S 1 1 494 423 (Me)₂N—(CH₂)₂— H Cl 4-cis-Me-c-Hex C(Me)₂CH₂OH S 1 2 535 424 (Me)₂N—(CH₂)₂— H Cl 4,4-diMe-c-Hex C(Me)₂CH₂OH S 1 2 549 425 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)(CH₂OH)₂ S 1 2 537 426 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂N(Me) S 1 3 548 427 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OMe S 1 2 535 428 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OMOM S 1 2 565 429 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OBn S 1 2 611 430 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂O(i-Bu) S 1 2 577 431 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OPh S 1 2 597 432 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂SPh S 1 2 613 433 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OCOPh S 1 2 625 434 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OCO(c-Hex) S 1 2 631 435 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OCOBn S 1 2 639 436 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OCOBu S 1 2 605 437 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OCO(i-Pr) S 1 2 591 438 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂CH₂OCO(2,5- diF—Ph) S 1 2 661 439 (Me)₂N—(CH₂)₂— H Cl c-Hex C(Me)₂OAc S 1 2 563 440 (Me)₂N—(CH₂)₂— H Cl c-Hex 2-(HOCH₂)-1-(c-penten)-1-yl S 1 2 545 441 (Me)₂N—(CH₂)₂— H Cl c-Hex (3S)-3-(OH)-Pyd-1-yl S 1 2 534 442 (Me)₂N—(CH₂)₂— H Cl 2,3-diF—Ph C(Me)₂CH₂OH S 1 2 566 443 (Me)₂N—(CH₂)₂— H Cl 2,3-diF—Ph N(Me)₂ S 1 2 580 444 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Me)OMe 2 2 522 445 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₂F 2 2 552 446 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₃F 2 2 566 447 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₃OH 2 2 564 448 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₂OH 2 2 550 449 (Me)₂N—(CH₂)₂— H Cl c-Hex N(n-Pr)(CH₂)₂OH 2 2 564 450 (Me)₂N—(CH₂)₂— H Cl c-Hex N(i-Pr)(CH₂)₂OH 2 2 564 451 (Me)₂N—(CH₂)₂— H Cl c-Hex N[(CH₂)₂OH]₂ 2 2 566 452 (Me)₂N—(CH₂)₂— H Cl c-Hex N[(CH₂)₂OMe]₂ 2 2 594 453 (Me)₂N—(CH₂)₂— H Cl c-Hex (2R)-2-(HOCH₂)-Pyd-1-yl 2 2 562 454 (Me)₂N—(CH₂)₂— H Cl c-Hex 4-amino-Pid-1-yl 2 2 561 455 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Me)(CH₂)₂OH 2 2 536 456 (Me)₂N—(CH₂)₂— H Cl c-Hex N(Me)(CH₂)₂OMe 2 2 550 457 (Et)₂N—(CH₂)₂— H Cl c-Hex N(i-Pr)(CH₂)₂OH 2 2 592 458 (Et)₂N—(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₂OH 2 2 578 459 1-pyd-(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₂F 2 2 578 460 1-pyd-(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₃F 2 2 592 461 (R)-3-OBn-1-Pyd-(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₃F 2 1 698 462 (R)-3-OBn-1-Pyd-(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₂OH 2 1 682 463 [Me(i-Pr)]N—(CH₂)₂— H Cl c-Hex N(Et)(CH₂)₃F 2 2 594

Example 464 (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl Step A: (2R)-2-[2-(diethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA

To a solution of (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl(hydroxypivaloyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl, prepared in Example 394, (521 mg, 1 mmol) in DCM (5 mL) was added Dess-Martin reagent (4M in THF, 0.5 mL). After the reaction mixture was stirred at rt for 12 h, an aqueous Na₂S₂O₃ solution was added portionwise, and the aqueous NaHCO₃ solution was added when the reaction solution is clear. The organic layer was extracted with EtOAc, dried over MgSO₄, and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (610 mg, 85.1%).

MS[M+H]=519(M+1)

Step B: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2TFA prepared in Step A.

MS[M+H]=519(M+1)

Example 465 (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl Step A: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((1-methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA

To a solution of (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((2-formyl)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide 2HCl, prepared in Example 464, (704 mg, 1.00 mmol) in pyridine (5 mL) was methoxyamine (HCl salts, 167 mg, 2.00 mmol). After the reaction mixture was stirred at rt for 12 h, the solvent was removed in vacuo, and the residue was diluted with a saturated aqueous NaHCO₃ solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO₄ and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (500 mg, 91.2%).

MS[M+H]=617(M+1)

Step B: (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((1-methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide HCl

The title compound was prepared following the procedure described in Step D of Example 187 using (2R)-2-[2-(dimethylamino)ethyl]amino-N-{(3S)-3-[cyclohexyl((1-methoxyimino)isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide TFA prepared in Step A.

MS[M+H]=617(M+1)

Biological Assays

A. Binding Assay

The membrane fraction binding assay was used to identify competitive inhibitors of ¹²⁵I-NDP- -MSH binding to cloned human MCRs expressed in HEK cells.

Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in Φ150 mm culture dishes in DMEM (GIBCO-BRL) supplemented with 10% FBS, 200 ug/ml Geneticin (GIBCO-BRL), and antibiotics (penicillin and streptomycin) (GIBCO-BRL) in an atmosphere of 6% CO₂ at 37° C. When the cells were fully grown, the cells were washed once with 10 ml of Ca⁺⁺, Mg⁺⁺ free DPBS. The cells were incubated with 8 ml of Ca⁺⁺, Mg⁺⁺ free DPBS for 15-30 min at 37° C. until the cells were easily detached by triturating with pipette. The cells were harvested into 50 ml of conical tubes, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in 8 ml of Ca⁺⁺, Mg⁺⁺ free DPBS, and spun at 1500 rpm for 5 min. The supernatant was discarded, and pellets were resuspended in 3 ml of membrane preparation buffer (50 mM Tris, pH 7.2˜7.4, 4 ug/ml Leupeptin; 10 uM Phosphoramidon; 40 ug/ml Bacitracin; 5 ug/ml Aprotinin; 10 mM Pefabloc). The pellets were homogenized with dounce homogenizer (Bellco with type “B” glass pestle) using 10-12 strokes. The homogenate was centrifuged (Beckman XL-100K Ultracentrifuge, Rotor 45 Ti, 50 ml centrifuge tube) at 40,000 rpm (100,000×g) for 30 min at 4° C. The pellets were resuspended in 20 ml of membrane preparation buffer, and protein was determined by BCA assay kit (PIERCE). Aliquots were placed in tubes and stored at −80° C.

Membrane fraction was diluted with membrane binding buffer to make final 600 ug/ml, and 50 ul of membrane fraction containing 30 ug of membrane protein was added onto each well of 96-well assay plate. 25 ul of test compounds or 20 uM unlabelled NDP- -MSH (to make the final concentration at 5 uM) diluted with membrane binding buffer was added onto each well of 96-well assay plate. 25 ul of 0.4 nM ¹²⁵I-NDP- -MSH [NEN, Cat. # NEX352 (50 uCi), t_(1/2)=60 days] diluted with membrane binding buffer was added onto each well to make the final concentration of 0.1 nM. The resulting mixture was incubated for 2 h at rt. The reaction mixture was filtered with 96 well GF/C filter plate (Unifilter GF/C™, Packard) presoaked with 0.1% polyethleneimine for 30 min. The filter plate was washed 3 times with 200 ul of washing buffer (50 mM Tris pH 7.2; 20 mM NaCl) under vacuo at 8 “Hg. The filter was dried for 15 min at rt, and the bottom was sealed. 40 ul of Packard Microscint™-20 was added to each well. The top was sealed, and the radioactivity was quantitated in a Packard Topcount Microplate Scintillation Counter. The IC₅₀ was defined as the concentration of test compound that results in the half maximal inhibition of ¹²⁵I-NDP- -MSH binding to cloned human MCRs. The IC₅₀ values obtained in the competition assay were converted to affinity constants (Ki values).

B. Functional Assay

1. Luciferase Assay.

Cell lines expressing human melanocortin receptor 4 (MC4R) were dissociated from tissue culture dishes by rinsing with Ca⁺⁺, Mg⁺⁺ free DPBS, treated with 1× Trypsin/EDTA solution for 1 min at 37° C., and resuspended with DMEM (GIBCO-BRL) supplemented with 10% FBS. The cells were counted and diluted with DMEM supplemented with 10% FBS and 200 ug/ml of Geneticin to 5×10⁵ cells/ml. 90 ul of cell suspension was plated onto each well of 96-well black and clear bottom culture plates (Costar). After the incubation for 24 h in the atmosphere of 6% CO₂ at 37° C., 10 ul of NDP- -MSH and test compounds diluted in DMSO were added to each well. The final DMSO concentration was 1%. After 4 h of incubation in the atmosphere of 6% CO₂ at 37° C., 50 ul of Bright-Glo (Promega) was added to each well. Luciferase activity was measured by using L-Max luminometer (Molecular Device). The amount of luciferase activity induced by treatment with NDP- -MSH was defined as 100% to obtain the relative efficacy of test compounds. The EC_(0.5 MSH) was defined as the concentration of test compounds that results in half maximal activity of NDP- -MSH. The EC₅₀ was defined as the concentration of test compound that results in half maximal activity of its own.

2. cAMP Accumulation Assay.

The membrane fraction cAMP assay was used to identify MC4R agonist compounds.

Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in Φ150 mm culture dishes in DMEM (GIBCO-BRL) supplemented with 10% FBS, 200 ug/ml Geneticin (GIBCO-BRL), and antibiotics (penicillin and streptomycin) (GIBCO-BRL) in an atmosphere of 6% CO₂ at 37° C. When the cells were fully grown, the cells were washed once with 10 ml of Ca⁺⁺, Mg⁺⁺ free DPBS. The cells were incubated with 8 ml of Ca⁺⁺, Mg⁺⁺ free DPBS for 15-30 min at 37° C. until the cells were easily detached by triturating with pipette. The cells were harvested into 50 ml of conical tubes, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in 8 ml of Ca⁺⁺, Mg⁺⁺ free DPBS, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the pellets were resuspended in 3 ml of membrane preparation buffer (10 mM Tris pH 7.4; 0.32M sucrose; 4 ug/ml leupeptin; 10 uM phosphoramidon; 40 ug/ml bacitracin; 5 ug/ml aprotinin). The pellets were homogenized with dounce homogenizer (Bellco with type “B” glass pestle) using 20 strokes. The homogenate was centrifuged at 1300×g at 4° C. for 10 min. The supernatants were collected, and the pellets were resuspended in membrane preparation buffer, and homogenization and centrifugation were repeated. All of the supernatants were collected and centrifuged at 40,000 rpm (Beckman XL-100K Ultracentrifuge, Rotor 45 Ti, 50 ml centrifuge tube) at 4° C. for 15 min. The pellets were resuspended in membrane preparation buffer, and protein was determined by BCA assay kit (PIERCE). Aliquots were placed in tubes and stored at −80° C.

20 ul of NDP- -MSH or test compounds diluted in DMSO were added onto each well of 96 well V-plate. 20 ul of 750 ug/ml membrane fraction in MP buffer was added onto each well. After the reaction was performed at rt for 15 min, cAMP was measured using cAMP (³H) assay Kit (Amersham, cat. No. TRK 432). The amount of cAMP produced by the treatment with test compound was compared to that produced in the response to NDP- -MSH which was defined as 100% agonist. The EC₅₀ was defined as the concentration of test compound that results in half maximal activity of its own.

As can be seen from the above results, the compounds according to the present invention showed agonistic efficacy and binding affinity to each MCR. In particular, the compounds according to the present invention showed excellent agonistic efficacy and binding affinity to the MCR4. i.e., 0.005 μM-10 μM of EC₅₀ value and 0.01 μM-50 μM of IC₅₀ value. For example, the compounds of examples 1, 2 and 3 showed 0.005 μM-0.5 μM of EC₅₀ value, and 0.1 μM-0.5 μM of IC₅₀ value, against MCR4.

C. In Vivo Food Intake Models

1. Hypophasic Effects in Fasted Mice

Hypophasic effects of melanocortinergic ligands are determined by using the food-deprived mouse model (male ddY mice). The animals are individually housed. One day before treatment, the animals are grouped (7-10 animals/group), based on their basal daily food intakes, and then their food is removed for 20 h fasting before treatment. In the morning of the test day, each animal receives the administration of vehicle or test substance via oral gavage, and 1 h after, food is re-supplied. Food intakes after the food-supply are measured for the first 1 h period.

2. Effects on Nocturnal Food Intake

Effects on nocturnal food intake are determined in male ICR mice. The animals are housed individually, and are grouped (7-10 animals/group) based on their basal daily food intakes. Each animal receives the administration of vehicle or test substance via oral gavage 1 h before starting the dark phase, and food is removed. Food is resupplied 1 h after the administration, and food intakes are measured at 1, 2, 4, 8, 24 h after the food is supplied.

3. Effects on Food Intake and Body Weight Change in Ob/Ob Mice

Effects on food intake and body weight change are determined in male 8 wks old ob/ob mice. The animals are housed individually, and are grouped (7-10 animals/group) based on their basal body weights. Each animal receives the administration of vehicle or test substance via oral gavage once a day for 14 days. Food intakes and body weigh changes are measured daily.

4. Effects on Food Intake and Body Weight Change in Diet-Induced Obese (DIO) Mice

Effects on food intake and body weight change are determined in male DIO mice. The DIO mice are prepared by feeding C57BL/6 mice on high fat diet for more than 8 weeks. The DIO animals are housed individually, and are grouped (7-10 animals/group) based on their basal body weights. Each animal receives the administration of vehicle or test substance via oral gavage once a day for 14 days. Food intakes and body weigh changes are measured daily.

D. Anti-Inflammatory Effects in an Acute Inflammation Model

Anti-inflammatory effects are determined as the effects on crystal-induced Polymorphonuclear Neutrophil (PMN) rec met. Each Balb/c mouse receives the administration of vehicle or test substance via oral gavage. One hour after the vehicle or drug treatment, the animals receive 3 mg of mono-sodium urea crystals in 0.5 ml of PBS (H 7.4) buffer (time=0) by the intraperitoneal injection. At 6 hs after the crystal injection, the animals are euthanized by CO₂ exposure, and then their peritoneal cavities are washed with 3 ml of PBS buffer. Aliquots of the lavage fluids are stained with Turk's solution (0.01% crystal violet in 3% acetic acid), and the number of cells are counted by using a hemacytometer and a light microscope. PMNs are counted as many as (1˜10)×10⁶ per mouse. Data are presented as 10⁶ PMN per mouse.

E. Erectile Effects

The erectile effect of the test substance is determined by counting the number of erection of male Sprague Dawley rats. Each animal receives the administration of vehicle or test substance via oral gavage 30 min before the test session, and then is placed in a 2-liter glass beaker. The beakers are located on an observation box designed for the ventral view of the animals. The number of erection is counted by observing the posture of the animals (hip constriction, hip thust, tiptoe posture) for 1 h. 

1. A compound of the following formula (1):

in which m and n each independently represents 2, R¹ represents hydrogen; heterocycle which is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and which is unsubstituted, or mono- or polysubstituted by substituents selected from halogen and C₁-C₁₀-alkyl; —(CH₂)₁₋₃—R⁶, wherein R⁶ is selected from the group consisting of hydrogen, C₁-C₁₀-alkyl, C₁-C₈-alkoxy, heterocycle, hydroxy, C₁-C₈-alkoxylcarbonyl, carboxy, amino, C₁-C₁₀-alkylamino, di(C₁-C₁₀-alkyl)amino, and C₁-C₈-alkylcarbonylamino, wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is substituted by one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C₁-C₁₀-alkyl, C₁-C₈-alkylcarbonyl and C₆-C₁₀-aryloxy; glycine, alanine, histidine, phenylalanine or proline, wherein one or more hydrogen atoms on nitrogen atom are unsubstituted or substituted by a substituent selected from the group consisting of C₁-C₁₀-alkyl, C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl and C₁-C₈-alkylsulfonyl; or —SO₂—C₁-C₃-alkyl, R² represents hydrogen; C₁-C₈-alkyl; —CO—(CH₂)₁₋₃-hydroxy; or —CH₂—CO-hydroxy, R³ represents C₁-C₈-alkyl which is unsubstituted, or mono- or polysubstituted by substituents selected from C₁-C₈-alkyl and carbamoyl; —(CH₂)₁₋₃—C₃-C₈-cycloalkyl; or —(CH₂)₀₋₃—C₆-C₁₀-aryl which is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, hydroxy, C₁-C₈-alkoxy and C₁-C₈-alkyl, R⁴ represents C₁-C₈-alkyl; —(CH₂)₁₋₃—C₃-C₈-cycloalkyl; C₃-C₈-cycloalkyl which is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, C₁-C₈-alkyl and C₆-C₁₀-aryl; or heterocycle which is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring, R⁵ represents carbonyl substituted by a substituent selected from the group consisting of C₁-C₈-alkyl, C₁-C₆ alkoxy, C₃-C₇-cycloalkyl, heterocycle and C₆-C₁₀-aryl unsubstituted or substituted by hydroxyl, wherein alkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino, hydroxy, C₁-C₈-alkoxy, C₆-C₁₀-ar-C₁-C₈-alkyloxy, C₁-C₈-alkyl C₆-C₁₀-aryloxy, C₆-C₁₀-aryloxy, C₆-C₁₀-arylthio, formyl, C₂-C₈-alkanoyloxy, C₃-C₈-cycloalkylcarbonyloxy, C₆-C₁₀-arylcarbonyloxy unsubstituted or substituted by halogen, C₆-C₁₀-ar-C₁-C₈-alkylcarbonyloxy; cycloalkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of hydroxycarbonyl, C₁-C₈-alkoxycarbonyl, hydroxyl-C₁-C₈alkyl, and wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is unsubstituted, or mono- or polysubstituted by the substituents selected from the group consisting of hydroxy, hydroxyC₁-C₈-alkyl, amino and 2-nitrobenzenesulfonyl; —(CH₂)₁₋₃—C(═O)—C₁-C₆-alkoxy; carbamoyl which is mono- or polysubstituted by substituents selected from the group consisting of hydrogen, C₁-C₈-alkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyl, C₆-C₁₀-aryl and C₁-C₈-alkylcarbonyl substituted by hydroxy, wherein alkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, hydroxy, amino and C₁-C₈-alkoxy; —(CH₂)₁₋₃—C(═O)N(C₁-C₈-alkyl)(C₁-C₈-alkyl); —C(═S)N(H)(C₁-C₈-alkyl) or —C(═S)N(H)(C₁-C₈-alkyl)(C₁-C₈-alkyl); or —SO₂—NH₂ or —(CH₂)₀₋₃—SO₂—C₁-C₈alkyl, wherein heterocycle can be fused with benzo or C₃-C₈-cycloalkyl, and which is saturated or has 1 or 2 double bond, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
 2. The compound according to claim 1, wherein R¹ represents hydrogen; or —(CH₂)₁₋₃—R⁶, wherein R⁶ selected from the group consisting of hydrogen, C₁-C₁₀-alkyl, C₁-C₈-alkoxy, heterocycle, hydroxy, C₁-C₈-alkoxylcarbonyl, carboxy, amino, C₁-C₁₀-alkylamino, di(C₁-C₁₀-alkyl)amino, and C₁-C₈-alkylcarbonylamino, wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is substituted by one or more substituents selected from the group consisting of halogen, oxo, hydroxy, C₁-C₁₀-alkyl, C₁-C₈-alkylcarbonyl and C₆-C₁₀-aryloxy; or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
 3. The compound according to claim 1, wherein R² represents hydrogen or C₁-C₆-alkyl, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
 4. The compound according to claim 1, wherein R³ represents —CH₂-phenyl which is unsubstituted or mono- to tri-substituted by substituents selected from the group consisting of chloro, bromo, hydroxy, methoxy and methyl, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
 5. The compound according to claim 1, wherein R⁴ represents C₃-C₈-cycloalkyl which is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of halogen, C₁-C₈-alkyl and C₆-C₁₀-aryl, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
 6. The compound according to claim 1, wherein R⁵ represents carbonyl substituted by the substituent selected from the group consisting of C₁-C₈-alkyl, C₁-C₆-alkoxy, C₃-C₇-cycloalkyl, heterocycle and C₆-C₁₀-aryl unsubstituted or substituted by hydroxyl, wherein alkyl is unsubstituted, or mono- or polysubstituted by the substituents selected from the group consisting of amino, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, hydroxy, C₁-C₈-alkoxy, C₆-C₁₀-ar C₁-C₈-alkyloxy, C₁-C₈-alkyl C₆-C₁₀-aryloxy, C₆-C₁₀-aryloxy, C₆-C₁₀-arylthio, formyl, C₂-C₈-alkanoyloxy, C₃-C₈-cycloalkylcarbonyloxy, C₆-C₁₀-arylcarbonyloxy unsubstituted or substituted by halogen, C₆-C₁₀-ar-C₁-C₈-alkylcarbonyloxy; cycloalkyl is unsubstituted, or mono- or polysubstituted by substituents selected from the group consisting of hydroxycarbonyl, C₁-C₈-alkoxycarbonyl, hydroxyl-C₁-C₈-alkyl, and wherein heterocycle is selected from the group consisting of morpholine, pyrrolidine, piperidine, furan and tetrahydroisoquinoline ring and is unsubstituted, or mono- or polysubstituted by the substituents selected from the group consisting of hydroxy, hydroxyC₁-C₈-alkyl, amino and 2-nitrobenzenesulfonyl, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
 7. An agonistic composition of melanocortin receptor comprising the compound of formula (1), or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof as defined in claim 1 together with a pharmaceutically acceptable carrier. 